Polyglutamine Disease Toxicity Is Regulated by Nemo-like Kinase in Spinocerebellar Ataxia Type 1
Open accessAbstract
Polyglutamine diseases are dominantly inherited neurodegenerative diseases caused by an expansion of a CAG trinucleotide repeat encoding a glutamine tract in the respective disease-causing proteins. Extensive studies have been performed to unravel disease pathogenesis and to develop therapeutics. Here, we report on several lines of evidence demonstrating that Nemo-like kinase (NLK) is a key molecule modulating disease toxicity in spinocerebellar ataxia type 1 (SCA1), a disease caused by a polyglutamine expansion in the protein ATAXIN1 (ATXN1). Specifically, we show that NLK, a serine/threonine kinase that interacts with ATXN1, modulates disease phenotypes of polyglutamine-expanded ATXN1 in a Drosophila model of SCA1. Importantly, the effect of NLK on SCA1 pathology is dependent upon NLK's enzymatic activity. Consistent with this, reduced Nlk expression suppresses the behavioral and neuropathological phenotypes in SCA1 knock-in mice. These data clearly indicate that either reducing NLK enzymatic activity or decreasing NLK expression levels can have beneficial effects against the toxicity induced by polyglutamine-expanded ATXN1.
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Written from the paper’s full text.
TL;DR
NLK physically interacts with ATXN1, phosphorylates ATXN1 at S/T-P sites including S239 in cell culture, and modulates polyglutamine-expanded ATXN1 toxicity in Drosophila and SCA1 knock-in mice. Reducing Nlk expression rescues motor and cerebellar phenotypes in Atxn1154Q/+ mice, and NLK’s effects require its kinase activity.
Key findings
- NLK interacts with the ATXN1 N-terminal region (amino acids #1–575) and phosphorylates ATXN1 at MAPK-like S/T-P sites; the S239A mutation strongly reduced NLK-mediated ATXN1 phosphorylation, while full-length ATXN1-S239A still showed slight NLK-dependent migration change, suggesting an additional C-terminal site.
- In a Drosophila SCA1 model at 27.5°C, heterozygous loss of one nmo allele strongly suppressed retinal depigmentation and ommatidial disorganization; coexpression of wild-type human NLK enhanced ommatidial disorganization, retinal degeneration, and necrotic cell death, whereas kinase-inactive NLK had little effect.
- In SCA1 knock-in Atxn1154Q/+ mice, loss of one Nlk allele almost completely rescued the dowel rod walking phenotype at 9–10 weeks and improved Purkinje cell dendritic arborization and molecular layer thickness at 38–39 weeks. Nlk gene trap lines showed an approximately 90% reduction in NLK expression in NlkRRJ297/XN619 cerebellum.
- NLK did not notably change ATXN1 expression or ATXN1 incorporation into large toxic complexes, but NLK strongly abolished ATXN1/CIC-mediated transcriptional repression in a luciferase reporter assay, and this effect required NLK kinase activity.
Methods
- Biochemical and cell-culture assays: co-affinity purification and co-immunoprecipitation in HEK293T cells or mouse brain extracts, western blotting, gel-filtration column fractionation, and a CIC-responsive luciferase reporter assay with ATXN1(82Q), CIC-S, and wild-type or kinase-inactive NLK.
- Drosophila studies: SCA1 model expressing polyglutamine-expanded ATXN1(82Q) in the eye, genetic interaction with nmo, and transgenic UAS-NLK wild-type or kinase-inactive KN lines.
- Mouse studies: Nlk gene trap lines RRJ297 and XN619 on C57BL/6J, crossed with SCA1 knock-in Atxn1154Q/+ mice; dowel rod walking at 9–10 weeks; calbindin immunofluorescence and confocal analysis of Purkinje cell dendritic arborization and molecular layer thickness at 38–39 weeks; ANOVA or two-tailed Student’s t-test.
Limitations
- Stated: the NLK–ATXN1 interaction may be transient in vivo, as co-IP from mouse brain extracts did not detect a strong interaction; endogenous Nlk expression patterns could not be detected by immunofluorescence, so LacZ staining was used instead; rotarod testing was precluded because Nlk heterozygotes showed impaired performance; further studies are needed to validate whether NLK phosphorylates ATXN1-S239 in vivo and how S239 phosphorylation affects ATXN1 function and SCA1 pathogenesis.
- Evident: the phosphorylation and transcriptional findings are largely from HEK293T cell culture, the Drosophila work uses overexpression, and the mouse genetic rescue tests Nlk haploinsufficiency rather than pharmacological NLK inhibition or complete NLK loss; direct in vivo evidence for NLK-mediated S239 phosphorylation is not provided.
Model-written summary. Check it against the paper before relying on it.
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Cites
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Claims the paper makes
20 of 46 cited sources checked · 8 supported · 0 flagged · accuracy not yet measured
- Premisecitation
S239 was identified as an in vivo ATXN1 phosphorylation site in multiple tissues, including brain, by mass-spectrometry analysis.
“One of these sites is serine 239 (S239), which was identified as an in vivo ATXN1 phosphorylation site in multiple tissues, including brain, by mass-spectrometry analysis (Vierra-Green et al., 2005; Huttlin et al., 2010).”
Quote in the paperSubstantial claim1 of 2 sources checked- cites Vierra-Green et al., 2005
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Huttlin et al., 2010 source
The Experimental Procedures describe LC-MS/MS analysis of phosphopeptides from nine mouse organs, including brain, and the Results discuss phosphorylation across tissues. But our copy does not identify ATXN1 S239 or say that this site was found in multiple tissues; searches for ATXN1, ataxin-1, and S239 found no matching passage. (LLM, conf=0.72)
Experimental — accuracy not yet measured
- Premisecitation
CIC family proteins play a key role in modulating ATXN1 functions and SCA1 pathogenesis.
“the CIC family proteins play a key role in modulating ATXN1 functions and SCA1 pathogenesis (Lam et al., 2006; Bowman et al., 2007; Lim et al., 2008; Fryer et al., 2011; Lee et al., 2011)”
Quote in the paperSubstantial claim1 of 3 sources checked - Premisecitation
Alterations in gene expression is the earliest pathological finding in SCA1 disease.
“alterations in gene expression is the earliest pathological finding in SCA1 disease (Lin et al., 2000; Serra et al., 2004; Cvetanovic et al., 2007; Crespo-Barreto et al., 2010; Cvetanovic et al., 2011; Fryer et al., 2011)”
Quote in the paperSubstantial claim1 of 3 sources checked- cites Lin et al., 2000 source
- cites Serra et al., 2004 source
- cites Cvetanovic et al., 2007 source
The Introduction calls transcriptional misregulation the earliest pathological change identified in SCA1 mice. The cited sentence extends that finding to SCA1 disease generally, without the mouse-model qualifier. (LLM, conf=0.85)
Experimental — accuracy not yet measured
- Findingown data
Transfection of full-length ATXN1 leads to production of an approximately 55kDa truncated ATXN1 fragment within cells.
“In addition, we found that transfection of the full-length ATXN1 also led to the production of an approximately 55kDa truncated ATXN1 fragment within cells, and the phosphorylation of this N-terminal fragment was also increased by wild-type, but not kinase-inactive NLK (Fig. 2A, arrowhead).”
Quote in the paperNot a substantial claim - Findingown data
All four genotypes tested remained on the dowel for the maximum time.
“All four genotypes tested remained on the dowel for the maximum time (data not shown).”
Quote in the paperNot a substantial claim
- Findingown data
The ATXN1 N-terminal region (amino acids 1-575) interacts best with NLK.
“we next determined the domains responsible for the interaction using a series of ATXN1 deletion constructs and found that the ATXN1 N-terminal region (amino acids #1–575) interacted best with NLK (Fig. 1B).”
Quote in the paperNot a substantial claim - Findingown data
NLK interacts with ATXN1 regardless of the phosphorylation status of S776 in mammalian cells.
“Again, NLK interacted well with ATXN1 regardless of the phosphorylation status of S776 in mammalian cells (data not shown).”
Quote in the paperNot a substantial claim - Findingown data
NLK phosphorylates ATXN1.
“NLK phosphorylates ATXN1”
- Also stated in: § NLK phosphorylates ATXN1 · boosted
“We found that wild-type NLK strongly induced the phosphorylation of ATXN1 (Fig. 2A, lane 2, arrow), while the kinase-inactive mutant did not (Fig. 2A, lane 3).”
Quote in the paperSubstantial claim - Also stated in: § NLK phosphorylates ATXN1 · boosted
- Findingown data
Immunofluorescence staining with available NLK antibodies failed to detect specific endogenous Nlk expression patterns in wild-type and NlkRRJ297/XN619 mice.
“We performed immunofluorescence staining using currently available NLK antibodies on the wild-type (positive control) and NlkRRJ297/XN619 (negative control) mice but failed to detect specific endogenous Nlk expression patterns (data not shown).”
Quote in the paperNot a substantial claim - Findingown data
Loss of one Nlk allele almost completely rescues the phenotypes of Atxn1154Q/+ mice back to wild-type and Nlk heterozygote levels.
“loss of just one Nlk allele almost completely rescued the phenotypes of Atxn1154Q/+ mice back to wild-type and Nlk heterozygote levels.”
Quote in the paperSubstantial claim - Findingown data
Atxn1154Q/+; Nlk+/− mice show significant improvement in molecular layer thickness compared to Atxn1154Q/+ mice alone at 38 to 39 weeks.
“Atxn1154Q/+; Nlk+/− mice showed a significant improvement in the molecular layer thickness, compared to Atxn1154Q/+ mice alone (Fig. 5D).”
Quote in the paperSubstantial claim - Findingown data
LacZ staining is strongest in the Purkinje cell layer.
“we analyzed Nlk expression by LacZ staining and found that LacZ staining was strongest in the Purkinje cell layer (Fig.4D)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Lein et al., 2007 source
- Findingown data
Expression of human NLK alone in the Drosophila eye does not cause major external morphological phenotypes at 27.5°C.
“Expression of human NLK alone in the Drosophila eye did not cause any major external morphological phenotypes at 27.5°C (data not shown).”
Quote in the paperSubstantial claim - Findingown data
NLK physically interacts with ATXN1.
“NLK physically interacts with ATXN1”
- Also stated in: § NLK physically interacts with ATXN1 · plain
“We discovered NLK as an ATXN1 interactor using a yeast two-hybrid screen as part of our efforts to develop an interactome for inherited ataxias (Lim et al., 2006).”
- Also stated in: § NLK physically interacts with ATXN1 · hedged
“We found that wild-type ATXN1(30Q) pulled down both wild-type NLK and the kinase-inactive NLK-KN (Fig. 1A), suggesting that the two proteins interact physically in mammalian cells.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Lim et al., 2006 source
- Also stated in: § NLK physically interacts with ATXN1 · plain
- Findingown data
Nlk heterozygote mice do not show obvious difference on the dowel rod test compared to wild-type littermates.
“The Nlk heterozygote mice did not show any obvious difference on the dowel rod test compared to their wild-type littermates.”
Quote in the paperNot a substantial claim - Findingown data
NlkRRJ297/XN619 cerebellum shows approximately 90% reduction in NLK expression compared to wild-type.
“Compared to wild-type cerebellum, NlkRRJ297/XN619 cerebellum shows an approximately 90% reduction in NLK expression (Fig. 4C)”
Quote in the paperSubstantial claim - Findingown data
Phosphorylation of the N-terminal fragment of ATXN1-S239A was completely abolished.
“Furthermore, while the phosphorylation of full-length ATXN1-S239A was decreased (Fig. 2B, arrow), the phosphorylation of the N-terminal fragment of ATXN1-S239A was completely abolished (Fig. 2B, arrowhead).”
Quote in the paperSubstantial claim - Findingown data
NLK expression is strongly reduced in both Nlk gene trap mouse lines (RRJ297 and XN619).
“Correct targeting of the gene trap alleles was confirmed by western blot, which showed that NLK expression was strongly reduced in both Nlk gene trap mouse lines (Fig. 4C).”
Quote in the paperSubstantial claim - Findingown data
Serine 239 (S239) is an NLK phosphorylation site on ATXN1.
“We found that the S239A mutation strongly reduced NLK-mediated ATXN1 phosphorylation (Fig. 2B, compare lane 3 with lane 7), suggesting that the S239 residue is a NLK phosphorylation site.”
Quote in the paperSubstantial claim - Findingown data
Kinase-inactive NLK has little effect when coexpressed with ATXN1(82Q).
“In contrast, kinase-inactive NLK had little effect when coexpressed with ATXN1(82Q) (Fig. 3L,N).”
Quote in the paperSubstantial claim - Findingown data
There is no notable change in expression of polyglutamine-expanded and wild-type ATXN1 and its associated proteins in mouse cerebellum when NLK is expressed at 50% of wild-type levels.
“We found that there was no notable change in the expression of these proteins in mouse cerebellum when NLK is expressed at 50% of wild-type levels (Fig. 6A).”
Quote in the paperSubstantial claim - Findingown data
Atxn1154Q/+ mice lacking one functional copy of Nlk display improved complexity of fine dendritic arbors and Purkinje cell soma at 38 to 39 weeks of age.
“Atxn1154Q/+ mice that lack one functional copy of Nlk displayed an improved complexity of fine dendritic arbors and Purkinje cell soma at 38 to 39 weeks of age, as examined by measuring calbindin immunofluorescence (Fig. 5B,C).”
Quote in the paperSubstantial claim - Findingown data
Splicing of the Nlk gene trap results in an mRNA transcript containing only the first one or two exons of Nlk followed by the βgeo sequence, excluding the majority of the NLK protein including the kinase domain.
“Splicing of the trap into Nlk results in an mRNA transcript that contains only the first one or two exons of Nlk followed by the βgeo (β-galactosidase-Neomycin) sequence, thereby excluding the majority of the NLK protein, including the kinase domain.”
Quote in the paperSubstantial claim - Findingown data
Nlk heterozygote mice display impaired performance on the rotarod on pure C57BL/6J background.
“We found that Nlk heterozygote (NlkRRJ297/+ or Nlk+/−) mice displayed an impaired performance on the rotarod on the pure C57BL/6J background (data not shown)”
Quote in the paperSubstantial claim - Findingown data
NLK interacts equally well with both wild-type and polyglutamine-expanded mutant ATXN1 in mammalian cells.
“We found that NLK interacted equally well with both wild-type and polyglutamine-expanded mutant ATXN1 by co-AP assays in mammalian cells (data not shown).”
Quote in the paperNot a substantial claim - Findingown data
Reduced Nlk expression suppresses the behavioral and neuropathological phenotypes in SCA1 knock-in mice.
“Consistent with this, reduced Nlk expression suppresses the behavioral and neuropathological phenotypes in SCA1 knock-in mice.”
- Also stated in: § Decreased NLK expression improves the SCA1 motor phenotype and cerebellar neuropathology in mice · plain
“Decreased NLK expression improves the SCA1 motor phenotype and cerebellar neuropathology in mice”
Quote in the paperSubstantial claim - Also stated in: § Decreased NLK expression improves the SCA1 motor phenotype and cerebellar neuropathology in mice · plain
- Findingown data
Coexpression of wild-type NLK dramatically increases the number and size of areas of necrotic cell death on external eyes of flies expressing ATXN1(82Q).
“In particular, coexpression of wild-type NLK led to a dramatic increase in the number and size of the areas of necrotic cell death seen on the external eyes of flies expressing ATXN1(82Q) (Fig. 3K,N, arrow).”
Quote in the paperSubstantial claim - Findingown data
Heterozygous loss of one nmo allele strongly suppresses retinal depigmentation and ommatidial disorganization phenotypes of SCA1 flies at 27.5°C.
“A heterozygous loss of one nmo allele strongly suppressed retinal depigmentation and ommatidial disorganization phenotypes of SCA1 flies when raised at 27.5°C (Fig. 3C,D,G,H,M), a temperature at which polyglutamine-expanded mutant ATXN1(82Q) causes only moderate retinal degeneration (Fig. 3B,F).”
Quote in the paperSubstantial claim - Findingown data
The effect of NLK on the ATXN1/CIC complex requires NLK's kinase activity.
“The effect of NLK on the ATXN1/CIC complex required NLK’s kinase activity.”
Quote in the paperSubstantial claim - Findingown data
N-terminal fragments of NLK are produced as fusion proteins to β-galactosidase in both RRJ297 and XN619 allele-bearing mice.
“there are N-terminal fragments of NLK produced as fusion proteins to β-galactosidase in both RRJ297 and XN619 allele-bearing mice (Fig. 4C).”
Quote in the paperSubstantial claim - Findingown data
NLK strongly abolishes ATXN1/CIC-mediated repression activity in HEK293T cells.
“we coexpressed NLK with ATXN1/CIC and found that NLK strongly abolished the ATXN1/CIC-mediated repression activity in HEK293T cells (Fig. 7).”
Quote in the paperSubstantial claim - Findingown data
The elution profiles of known Atxn1-interacting proteins including CIC and Rbm17 are not altered in Atxn1154Q/+; Nlk+/− mice compared to Atxn1154Q/+ mice.
“the elution profiles of known Atxn1-interacting proteins including CIC and Rbm17 were also not altered in Atxn1154Q/+; Nlk+/− mice compared to Atxn1154Q/+ mice.”
Quote in the paperSubstantial claim - Findingown data
The elution profile of Nlk covers those of Atxn1 and its associated proteins CIC and Rbm17.
“The elution profile of Nlk covers those of Atxn1 and its associated proteins, Capicua (CIC) and RNA-binding motif protein 17 (Rbm17).”
Quote in the paperNot a substantial claim - Findingown data
NLK is able to induce phosphorylation of ATXN1, either directly or indirectly, on several conserved MAPK consensus sites including S239, at least in cell culture.
“Our biochemical studies suggest that NLK is able to induce the phosphorylation of ATXN1, either directly or indirectly, on several conserved MAPK consensus sites including S239, at least in cell culture system (Fig. 2).”
Quote in the paperSubstantial claim - Findingown data
The phosphorylation level of ATXN1 at residue S776 is not altered by NLK in cell culture and in mouse in vivo.
“the phosphorylation level of ATXN1 at residue S776 was not altered by NLK in cell culture and in mouse in vivo (data not shown)”
Quote in the paperSubstantial claim - Findingown data
Overexpression of NLK enhances disease phenotypes of polyglutamine-expanded ATXN1 in the Drosophila model in a kinase activity-dependent manner.
“overexpression of NLK enhances disease phenotypes of polyglutamine-expanded ATXN1 in the Drosophila model in a kinase activity-dependent manner.”
Quote in the paperSubstantial claim - Findingown data
A high level of Nlk protein is detected in much smaller complexes in fractions 14-15 in Atxn1154Q/+; Nlk+/− mice compared to Atxn1154Q/+ mice.
“a high level of the Nlk protein was detected in much smaller complexes in fractions 14–15 in Atxn1154Q/+; Nlk+/− mice compared to Atxn1154Q/+ mice (Fig. 6B, small blue box).”
Quote in the paperNot a substantial claim - Findingown data
The relative ratio of polyglutamine-expanded and wild-type Atxn1 incorporation into toxic large protein complexes is not significantly different between Atxn1154Q/+; Nlk+/− and Atxn1154Q/+ mouse cerebellum.
“the relative ratio of polyglutamine-expanded (as well as wild-type) Atxn1 incorporation into the toxic large protein complexes was not significantly different between Atxn1154Q/+; Nlk+/− and Atxn1154Q/+ mouse cerebellum (Fig. 6B).”
Quote in the paperSubstantial claim - Findingown data
The level of Nlk incorporation in toxic large complexes is low in Atxn1154Q/+; Nlk+/− mice compared to Atxn1154Q/+ mice.
“the level of Nlk incorporation in toxic large complexes was low in Atxn1154Q/+; Nlk+/− mice compared to Atxn1154Q/+ mice (Fig. 6B, red box).”
Quote in the paperSubstantial claim - Premisecitation
SCA1 is caused by expansion of a CAG repeat encoding a glutamine tract in the protein ATXN1.
“spinocerebellar ataxia type 1 (SCA1), a disease caused by a polyglutamine expansion in the protein ATAXIN1 (ATXN1).”
- Also stated in: § Introduction · plain
“SCA1 is caused by the expansion of a CAG repeat encoding a glutamine tract in the protein ATAXIN1 (ATXN1) (Orr et al., 1993).”
- Also stated in: § NLK physically interacts with ATXN1 · boosted
“the glutamine expansion is the central cause of SCA1 pathogenesis (Orr et al., 1993)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Orr et al., 1993 source
- Also stated in: § Introduction · plain
- Interpretationown data
NLK can phosphorylate ATXN1 at S/T-P site(s) in cell culture.
“This suggests that NLK can phosphorylate ATXN1 at S/T-P site(s) in our cell culture system.”
Quote in the paperSubstantial claim - Interpretationown data
NLK exacerbates the toxicity of polyglutamine-expanded ATXN1 in a Drosophila model of SCA1 in a kinase activity-dependent manner.
“Taken together, these studies indicate that NLK exacerbates the toxicity of polyglutamine-expanded ATXN1 in a Drosophila model of SCA1 in a kinase activity-dependent manner.”
- Also stated in: § Abstract · plain
“we show that NLK, a serine/threonine kinase that interacts with ATXN1, modulates disease phenotypes of polyglutamine-expanded ATXN1 in a Drosophila model of SCA1.”
- Also stated in: § Abstract · plain
“the effect of NLK on SCA1 pathology is dependent upon NLK’s enzymatic activity.”
Quote in the paperSubstantial claim - Also stated in: § Abstract · plain
- Interpretationown data
The NLK-ATXN1 interaction may be transient in vivo.
“We were not able to detect a strong physical interaction between Nlk and Atxn1 (mouse homologues of NLK and ATXN1, respectively) from brain extracts (data not shown), suggesting that the NLK and ATXN1 interaction may be transient in vivo.”
Quote in the paperNot a substantial claim - Interpretationown data
RRJ297 and XN619 are strong hypomorphic alleles.
“suggesting that RRJ297 and XN619 are strong hypomorphic alleles.”
Quote in the paperSubstantial claim - Premisecitation
The dendritic arborization defect of Purkinje cells is the most prominent pathological sign in aging Atxn1154Q/+ animals.
“The dendritic arborization defect of the Purkinje cells in the cerebellum is the most prominent pathological sign in aging Atxn1154Q/+ animals (Watase et al., 2002; Jafar-Nejad et al., 2011).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Watase et al., 2002 source
- cites Jafar-Nejad et al., 2011
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data
Decreased expression of NLK has beneficial effects against neuronal toxicity in SCA1.
“Using biochemical and cell biological studies, as well as genetic studies in Drosophila and mice, we demonstrated that decreased expression of NLK has beneficial effects against neuronal toxicity in SCA1.”
Quote in the paperSubstantial claim - Interpretationown data
Studies using biochemical approaches as well as a Drosophila model system demonstrate that NLK enhances SCA1 neuropathology in a kinase activity-dependent manner.
“Studies using biochemical approaches as well as a Drosophila model system demonstrate that NLK enhances SCA1 neuropathology in a kinase activity-dependent manner.”
Quote in the paperSubstantial claim - Interpretationown data
Decreasing NLK expression rescues the dowel phenotype caused by polyglutamine-expanded mutant ATXN1.
“Thus, decreasing NLK expression rescues the dowel phenotype caused by polyglutamine-expanded mutant ATXN1.”
Quote in the paperSubstantial claim- Rests on an assumption: The dowel rod walking test is a valid measure of motor coordination and balance defects relevant to SCA1 in mice.
- Interpretationown data
NLK is a key molecule modulating disease toxicity in SCA1.
“Here, we report on several lines of evidence demonstrating that Nemo-like kinase (NLK) is a key molecule modulating disease toxicity in spinocerebellar ataxia type 1 (SCA1), a disease caused by a polyglutamine expansion in the protein ATAXIN1 (ATXN1).”
Quote in the paperSubstantial claim - Interpretationown data
NLK is a key protein contributing to the pathogenesis of SCA1.
“we show that NLK is a key protein contributing to the pathogenesis of SCA1.”
Quote in the paperSubstantial claim- Rests on an assumption: The dowel rod walking test is a valid measure of motor coordination and balance defects relevant to SCA1 in mice.
- Rests on an assumption: The CIC-responsive luciferase reporter in HEK293T cells reflects the transcriptional activity of the ATXN1/CIC complex relevant to SCA1 pathogenesis.
- Interpretationown data
NLK can affect the transcriptional activity of the ATXN1/CIC protein complex.
“Our cell culture-based luciferase assay indicates that NLK can affect the transcriptional activity of the ATXN1/CIC protein complex (Fig. 7).”
Quote in the paperSubstantial claim- Rests on an assumption: The CIC-responsive luciferase reporter in HEK293T cells reflects the transcriptional activity of the ATXN1/CIC complex relevant to SCA1 pathogenesis.
- Interpretationown data
Reduced enzymatic activity or decreased expression of NLK can have beneficial effects against polyglutamine-expanded ATXN1 protein toxicity.
“Experimental evidence from two different SCA1 model systems, Drosophila and mice, strongly supports the idea that reduced enzymatic activity or decreased expression of NLK can have beneficial effects against polyglutamine-expanded ATXN1 protein toxicity.”
Quote in the paperSubstantial claim- Rests on an assumption: The dowel rod walking test is a valid measure of motor coordination and balance defects relevant to SCA1 in mice.
- Interpretationown data
The beneficial effects of decreased expression of NLK against SCA1 toxicity are not mediated by decreased S776-ATXN1 phosphorylation.
“indicating that the beneficial effects of decreased expression of NLK against SCA1 toxicity is not mediated by decreased S776-ATXN1 phosphorylation.”
Quote in the paperSubstantial claim - Interpretationown data
Nlk haploinsufficiency in SCA1 knock-in (Atxn1154Q/+) mice rescues SCA1 cerebellar pathology and motor phenotypes.
“we show that Nlk haploinsufficiency in the SCA1 knock-in (Atxn1154Q/+) mice rescues SCA1 cerebellar pathology and motor phenotypes.”
Quote in the paperSubstantial claim- Rests on an assumption: The dowel rod walking test is a valid measure of motor coordination and balance defects relevant to SCA1 in mice.
- Premisecitation
This transcriptional activity is important for the pathogenesis of SCA1.
“This transcriptional activity is important for the pathogenesis of SCA1 (Lin et al., 2000; Serra et al., 2004; Lam et al., 2006; Cvetanovic et al., 2007; Crespo-Barreto et al., 2010; Cvetanovic et al., 2011; Fryer et al., 2011).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationown data
NLK modulates the ATXN1/CIC transcription complex activity.
“These data provide evidence for the role of NLK in modulating the ATXN1/CIC transcription complex activity.”
Quote in the paperSubstantial claim- Rests on an assumption: The CIC-responsive luciferase reporter in HEK293T cells reflects the transcriptional activity of the ATXN1/CIC complex relevant to SCA1 pathogenesis.
- Interpretationown data
NLK may not impact the stability of Atxn1 and its known associated proteins in mice.
“Our finding that there was no notable change in the expression levels of Atxn1 and its known associated proteins in Nlk heterozygous mouse cerebellum (Fig. 6A) suggests that NLK may not impact the stability of these proteins in mice.”
Quote in the paperSubstantial claim - Interpretationown data
Decreased expression of Nlk in a Drosophila SCA1 model and in SCA1 knock-in (Atxn1154Q/+) mice rescues pathological and behavioral phenotypes of SCA1.
“our study clearly shows that decreased expression of Nlk in a Drosophila SCA1 model and in SCA1 knock-in (Atxn1154Q/+) mice rescues pathological and behavioral phenotypes of SCA1.”
Quote in the paperSubstantial claim- Rests on an assumption: The dowel rod walking test is a valid measure of motor coordination and balance defects relevant to SCA1 in mice.
- Interpretationown data
NLK may not play a substantial role in the formation and maintenance of the large toxic ATXN1 complexes in vivo.
“the fact that the formation and maintenance of ATXN1 protein complexes was not altered in a Nlk heterozygote background compared to Nlk wild-type mice (Fig. 6B) suggests that NLK may not play a substantial role in the formation and maintenance of the large toxic ATXN1 complexes in vivo.”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 11
- May combine two claims. 11
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationNLK is an evolutionarily conserved serine/threonine protein kinase.
“NLK is an evolutionarily conserved serine/threonine protein kinase (Choi and Benzer, 1994; Banfi et al., 1996; Brott et al., 1998; Meneghini et al., 1999).”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites Choi and Benzer, 1994 source
The Introduction (page not supplied) says that the Drosophila nemo (nmo) locus encodes a homolog of serine/threonine protein kinases. The passages do not establish that NLK is evolutionarily conserved across species, so they support the kinase description but not that qualifier. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites Banfi et al., 1996 source
- cites Brott et al., 1998 source
Classified as probably not a substantial claim. May combine two claims.
PremisecitationNeurodegeneration in SCA1 results from a gain of endogenous functions mediated by polyglutamine-expanded mutant ATXN1 and from a concurrent partial loss of the beneficial functions of wild-type ATXN1.
“in SCA1 results from a gain of endogenous functions mediated by the polyglutamine-expanded mutant ATXN1, and from a concurrent partial loss of the beneficial functions of wild-type ATXN1 (Lim et al., 2008; Crespo-Barreto et al., 2010; Fryer et al., 2011).”
Quote in the paperSubstantial claim3 of 3 sources checked- cites Lim et al., 2008 source
- cites Crespo-Barreto et al., 2010 source
- cites Fryer et al., 2011 source
The paper’s discussion (page unavailable in our copy) identifies a gain-of-function mechanism as the driver of SCA1 toxicity. It also reports a concurrent partial loss of Capicua’s normal repressor activity, but does not establish that the concurrent loss is of beneficial wild-type ATXN1 functions as the claim states. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim.
PremisecitationThe importance of a large ATXN1 protein complex for the pathogenesis of SCA1 is established.
“Having established the importance of a large ATXN1 protein complex for the pathogenesis of SCA1 (Lam et al., 2006; Bowman et al., 2007; Lim et al., 2008; Jafar-Nejad et al., 2011)”
Quote in the paperSubstantial claim1 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationS776 phosphorylation of ATXN1 is absolutely required for SCA1 pathogenesis.
“We also explored the possibility that the interaction between NLK and ATXN1 may depend on the phosphorylation status at serine 776 (S776) of ATXN1, a key feature that is absolutely required for SCA1 pathogenesis (Emamian et al., 2003; Duvick et al., 2010).”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites Emamian et al., 2003 source
No passage from our copy was returned for searches on S776 phosphorylation, disease, or ataxin-1. The paper’s title alone cannot establish that phosphorylation is absolutely required for SCA1 pathogenesis, so the claim cannot be verified from the available passages. (LLM, conf=0.69)
Experimental — accuracy not yet measured - cites Duvick et al., 2010 source
The Discussion (page unavailable) says a phosphomimetic substitution promotes disease and cites prior evidence that a phosphoresistant substitution prevents ataxia. But it presents S776 phosphorylation as a model for disease initiation and neuronal dysfunction that still needs a direct test; it does not establish that phosphorylation is absolutely required for all SCA1 pathogenesis. (LLM, conf=0.88)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationNLK-KN is a lysine to methionine substitution at residue 155 (K155M) and is defective for kinase activity.
“NLK-KN is a lysine to methionine substitution at residue 155 (K155M) and is defective for kinase activity (Ishitani et al., 2003; Ishitani et al., 2011).”
Quote in the paperSubstantial claim1 of 2 sources checked- cites Ishitani et al., 2003 source
- cites Ishitani et al., 2011
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
PremisecitationNLK is a MAPK-like kinase and targets the (S/T-P) consensus motif for phosphorylation.
“since it is a MAPK-like kinase (Brott et al., 1998) and therefore targets the (S/T-P) consensus motif for phosphorylation.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Brott et al., 1998 source
In “Isolation and Characterization of the Nlk cDNA” and the Discussion (page numbers not supplied), the paper describes Nlk as related to Erk/MAP kinases. It says Nlk may have proline-directed substrate specificity, but does not establish that it targets the (S/T-P) motif; the citing sentence states that inference as fact. (LLM, conf=0.86)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationATXN1 protein binds to CIC family transcription factors and regulates transcription of target genes in vitro and in vivo.
“The ATXN1 protein binds to the CIC family of transcription factors and regulates the transcription of target genes in vitro in cell culture systems (Lam et al., 2006) as well as in vivo in mice (Crespo-Barreto et al., 2010; Fryer et al., 2011).”
Quote in the paperSubstantial claim2 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPhosphorylation of polyglutamine disease proteins plays important roles in disease pathogenesis by affecting proteolytic cleavage, toxic conformational change, nuclear transport, and gene transcription.
“In neurodegenerative diseases, phosphorylation of polyglutamine disease proteins plays important roles in disease pathogenesis by affecting diverse aspects of pathogenicity including proteolytic cleavage, induction of a toxic conformational change, nuclear transport, and gene transcription (Bauer and Nukina, 2009; Pennuto et al., 2009).”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites Bauer and Nukina, 2009 source
- cites Pennuto et al., 2009 source
The Interplay Between Post-translational Modifications section (page not provided) says phosphorylation affects proteolytic cleavage of polyQ proteins, and the Phosphorylation section reports effects on their aggregation and toxicity. It does not establish induction of a toxic conformational change. Its examples of phosphorylation affecting nuclear transport and transcription concern androgen receptor in prostate cancer cells; the paper says it is unknown whether those phosphorylation sites affect polyQ androgen-receptor toxicity. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn SCA1, several phosphorylation sites have been identified in mouse brain in vivo including S776 and S239.
“In SCA1, several phosphorylation sites have been identified so far in mouse brain in vivo including S776 and S239 (Emamian et al., 2003; Vierra-Green et al., 2005; Huttlin et al., 2010).”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites Emamian et al., 2003 source
No passage from our copy was returned for searches on S776 or S239 phosphorylation in mouse brain, including searches for phosphorylation in vivo. The available indexed passages therefore do not establish which sites this paper identified. (LLM, conf=0.66)
Experimental — accuracy not yet measured - cites Vierra-Green et al., 2005
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Huttlin et al., 2010 source
The Results section on tissue distribution reports phosphorylation sites in mouse brain, but the passages from our copy do not identify SCA1/ataxin-1 sites S776 or S239. Searches for those site numbers, ataxin-1/Atxn1, and spinocerebellar ataxia found no passage addressing the specific claim; page numbers were not provided. (LLM, conf=0.72)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPhosphorylation of S776 in ATXN1 is crucial for the initiation and progression of SCA1.
“The phosphorylation of S776 in ATXN1 is extensively studied and is known to be crucial for the initiation and progression of SCA1 (Emamian et al., 2003; Duvick et al., 2010).”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites Emamian et al., 2003 source
No passage from our copy was provided or returned for searches on S776, phosphorylation, ataxin-1, and disease. Although the paper’s title concerns serine 776 and disease in SCA1 transgenic mice, the available passages do not establish what the paper says about phosphorylation or the initiation and progression of SCA1. (LLM, conf=0.65)
Experimental — accuracy not yet measured - cites Duvick et al., 2010 source
The Discussion says S776 phosphorylation drives disease initiation and the development of neuronal dysfunction. It also distinguishes those stages from later neuronal death, which requires an expanded polyglutamine tract. Thus, the unqualified claim about progression of SCA1 is broader than this paper supports. (LLM, conf=0.85)
Experimental — accuracy not yet measured
May combine two claims.
Findingown dataAtxn1154Q/+ mice have dramatically increased latency to reach the side for the first time and walk off the rod much fewer times compared to littermate controls.
“The latency of Atxn1154Q/+ mice to reach the side for the first time was dramatically increased compared to littermate control mice, and consequently they walked off the rod much fewer times.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAtxn1154Q/+; Nlk+/− mice take much less time to walk off the dowel and cross the dowel more times in 120 seconds than Atxn1154Q/+ littermates.
“The Atxn1154Q/+; Nlk+/− mice took much less time to walk off the dowel and also crossed the dowel more times in 120 seconds than Atxn1154Q/+ littermates.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
FindingcitationNlk gene-trap mice display phenotypes that vary depending on genetic background.
“Our Nlk gene-trap mice display phenotypes that vary depending on the genetic background, which is consistent with a previously reported Nlk knockout mouse (Kortenjann et al., 2001).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Kortenjann et al., 2001
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataAll proteins elute in a broad range with at least two peaks at fractions 7-9 (large complexes) and 11-12 (small complexes).
“all proteins elute in a broad range with at least two peaks at fractions 7–9 (red box, large protein complexes) and 11–12 (blue box, small protein complexes) (Fig. 6B).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationNLK proteins function as important regulators of cell growth, patterning, and death by controlling diverse signaling pathways including Wnt and Notch pathways.
“Across species, NLK proteins function as important regulators of cell growth, patterning, and death by controlling diverse signaling pathways including Wnt and Notch pathways (Ishitani et al., 1999; Meneghini et al., 1999; Rocheleau et al., 1999; Verheyen et al., 2001; Rottinger et al., 2006).”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
Interpretationown dataEither reducing NLK enzymatic activity or decreasing NLK expression levels can have beneficial effects against the toxicity induced by polyglutamine-expanded ATXN1.
“These data clearly indicate that either reducing NLK enzymatic activity or decreasing NLK expression levels can have beneficial effects against the toxicity induced by polyglutamine-expanded ATXN1.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataS239 is likely the only NLK phosphorylation site in N-terminal ATXN1 fragments, but there may be other NLK phosphorylation sites in the C-terminal region of ATXN1.
“This suggests that the S239 residue is likely the only NLK phosphorylation site in these N-terminal ATXN1 fragments, but there may be other putative targets for NLK phosphorylation in the C-terminal region of ATXN1.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationTargeted expression of polyglutamine-expanded mutant ATXN1 in the Drosophila eye causes retinal depigmentation, disruption of the structured eye pattern and retinal degeneration.
“we utilized a Drosophila model of SCA1 (Fernandez-Funez et al., 2000) in which targeted expression of polyglutamine-expanded mutant ATXN1 in the eye causes retinal depigmentation, disruption of the structured eye pattern and retinal degeneration (Fig. 3B,F,J).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Fernandez-Funez et al., 2000 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDisruption of the Nlk gene in mice results in diverse neuronal and non-neuronal phenotypes.
“Disruption of the Nlk gene in mice results in diverse neuronal and non-neuronal phenotypes (Kortenjann et al., 2001).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Kortenjann et al., 2001
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Interpretationown dataReducing NLK expression rescues the ataxic behavioral phenotype and cerebellar pathology caused by polyglutamine expansion in SCA1.
“Taken together, the gene dosage-dependent genetic interaction between NLK and mutant ATXN1 in mice strongly suggests that reducing NLK expression rescues the ataxic behavioral phenotype and cerebellar pathology caused by polyglutamine-expansion in SCA1.”
Quote in the paperSubstantial claim- Rests on an assumption: The dowel rod walking test is a valid measure of motor coordination and balance defects relevant to SCA1 in mice.
May combine two claims.
Interpretationown dataNLK may not play a significant role in the degradation of ATXN1 or in the formation and maintenance of the large toxic ATXN1 complexes in mice in vivo.
“Taken together, these data suggest that NLK may not play a significant role in the degradation of ATXN1 or in the formation and maintenance of the large toxic ATXN1 complexes in mice in vivo.”
Quote in the paperSubstantial claim
The paper relies on this without support.
The cellular and mechanistic basis by which loss of NLK function results in numerous neurological abnormalities has not been established.
“Despite its essential role in animal development, however, the cellular and mechanistic basis by which loss of NLK function results in numerous neurological abnormalities has not been established.”
The paper relies on this without support.
The dowel rod walking test is a valid measure of motor coordination and balance defects relevant to SCA1 in mice.
“as an alternative test for motor coordination and balance defects, we performed the dowel rod walking test at 9 to 10 weeks of age (Fig. 5A).”
The paper relies on this without support.
The CIC-responsive luciferase reporter in HEK293T cells reflects the transcriptional activity of the ATXN1/CIC complex relevant to SCA1 pathogenesis.
“we took advantage of the established CIC-responsive luciferase reporter, which is repressed by the ATXN1/CIC complex (Fig. 7).”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
NLK phosphorylates AR and ataxin-1, the proteins mutated to cause SBMA and SCA1, respectively.
“We have previously reported that NLK phosphorylates AR and ataxin-1, the proteins mutated to cause SBMA and SCA1, respectively”
From Reduction of nemo-like kinase increases lysosome biogenesis and ameliorates TDP-43–related neurodegeneration (2023) · cites this paper as [7]
The Results section, “NLK phosphorylates ATXN1” (page unavailable), reports that NLK induced ATXN1 phosphorylation in cultured cells; the Discussion notes that this could be direct or indirect. Our copy does not report NLK phosphorylating the androgen receptor (AR), so it supports only the ataxin-1 part of the claim. (LLM, conf=0.88)
Experimental — accuracy not yet measuredNLK depletion mitigates disease phenotypes in Drosophila and murine models of ALS, murine models of spinobulbar muscular atrophy, and murine models of spinocerebellar ataxia.
“NLK depletion mitigates disease phenotypes not just in Drosophila and murine models of ALS, but also murine models of spinobulbar muscular atrophy, and murine models of spinocerebellar ataxia (15–17).”
From Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS (2025) · cites this paper as [17]
The Results and Discussion report that reduced NLK expression mitigated disease phenotypes in Drosophila and mouse models of spinocerebellar ataxia type 1. Our copy does not report NLK-depletion outcomes in ALS or spinobulbar muscular atrophy models, so it supports only the SCA1 portion of the cited sentence. (LLM, conf=0.90)
Experimental — accuracy not yet measuredNlk haploinsufficiency (Nlk+/−) is protective in several neurodegenerative disease models, including TDP43-overexpressing mice.
“Conditional Nlk knockout in adult animals is well-tolerated, however (59), and Nlk haploinsufficiency (Nlk+/−) is protective in several neurodegenerative disease models, including TDP43-overexpressing mice (15–18).”
From Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS (2025) · cites this paper as [17]
The Results section reports that Nlk haploinsufficiency improved motor performance and cerebellar pathology in SCA1 knock-in mice. The Discussion likewise identifies SCA1 as the mouse disease model studied. Our copy does not support the broader claim about several neurodegenerative disease models or the specific example of TDP43-overexpressing mice. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPhosphorylation of AR and ataxin-1 contributes to pathogenicity.
“and that phosphorylation of these proteins contributes to pathogenicity (7, 8).”
From Reduction of nemo-like kinase increases lysosome biogenesis and ameliorates TDP-43–related neurodegeneration (2023) · cites this paper as [7]
NLK interacts with several proteins associated with neurodegenerative diseases, including poly-Q expanded androgen receptor in spinobulbar muscular atrophy (SBMA) and ataxin-1 in spinocerebellar ataxia 1 (SCA1).
“NLK interacts with several proteins associated with neurodegenerative diseases, including poly-Q expanded androgen receptor in spinobulbar muscular atrophy (SBMA) and ataxin-1 in spinocerebellar ataxia 1 (SCA1) (16, 17); accumulations of these proteins may also contribute to changes in NLK expression and/or activity.”
From Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS (2025) · cites this paper as [17]
NLK haploinsufficiency can rescue SCA1 cerebellar pathology and motor phenotypes.
“Using the NLK heterozygous SCA1 knock-in model, it was found that NLK haploinsufficiency can rescue SCA1 cerebellar pathology and motor phenotypes [50].”
From Nemo-Like Kinase in Development and Diseases: Insights from Mouse Studies (2020) · cites this paper as [50]
Decreased NLK expression might be beneficial against polyglutamine-expanded ATAXIN1 (ATXN1) protein toxicity.
“It was shown that decreased NLK expression might be beneficial against polyglutamine-expanded ATAXIN1 (ATXN1) protein toxicity.”
From Nemo-Like Kinase in Development and Diseases: Insights from Mouse Studies (2020) · cites this paper as [50]
Cites
Genome-wide atlas of gene expression in the adult mouse brain
Lein, E. S., Hawrylycz, M. J., Ao, N., Ayres, M., Bensinger, A., Bernard, A., Boe, A. F., Boguski, M. S., Brockway, K. S., Byrnes, E. J., et al. (2007) · Nature · doi:10.1038/nature05453 · Cited by 5,572 · see citing works
A tissue-specific atlas of mouse protein phosphorylation and expression
Huttlin, E. L., Jedrychowski, M. P., Elias, J. E., Goswami, T., Rad, R., Beausoleil, S. A., Villén, J., Haas, W., Sowa, M. E., & Gygi, S. P. (2010) · Cell · doi:10.1016/j.cell.2010.12.001 · Cited by 1,778 · cited 2× · see citing works
“One of these sites is serine 239 (S239), which was identified as an in vivo ATXN1 phosphorylation site in multiple tissues, including brain, by mass spectrometry analysis (Vierra-Green et al., 2005; Huttlin et al., 2010).”
BackgroundExpansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1
Orr, H. T., Chung, M.-Y., Banfi, S., Kwiatkowski, T. J., Servadio, A., Beaudet, A. L., McCall, A. E., Duvick, L. A., Ranum, L. P. W., & Zoghbi, H. Y. (1993) · Nature Genetics · doi:10.1038/ng0793-221 · Cited by 1,632 · cited 2× · see citing works
“SCA1 is caused by the expansion of a CAG repeat encoding a glutamine tract in the protein ATAXIN1 (ATXN1) (Orr et al., 1993).”
BackgroundSelf-citationTrinucleotide Repeat Disorders
Orr, H. T., & Zoghbi, H. Y. (2007) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.29.051605.113042 · Cited by 1,365 · cited 1× · see citing works
“The clinical features of SCA1 result from the degeneration of cerebellar Purkinje cells, brainstem cranial nerve nuclei and inferior olive neurons, and spinocerebellar tracts (Orr and Zoghbi, 2007).”
BackgroundSelf-citationLim, J., Hao, T., Shaw, C., Patel, A. J., Szabó, G., Rual, J.-F., Fisk, C. J., Li, N., Smolyar, A., Hill, D. E., et al. (2006) · Cell · doi:10.1016/j.cell.2006.03.032 · Cited by 789 · cited 4× · see citing works
“…understand the disease pathogenesis better and to identify an effector protein that can be potentially used as a therapeutic target in SCA1, we examined candidate proteins identified from our previous physical interaction or genetic modifier studies (Fernandez-Funez et al., 2000; Lim et al., 2006).”
BackgroundMethodInfluentialSelf-citationIdentification of genes that modify ataxin-1-induced neurodegeneration
Fernandez-Funez, P., Nino-Rosales, M. L., de Gouyon, B., She, W.-C., Luchak, J. M., Martinez, P., Turiegano, E., Benito, J., Capovilla, M., Skinner, P. J., et al. (2000) · Nature · doi:10.1038/35040584 · Cited by 661 · cited 2× · see citing works
“…understand the disease pathogenesis better and to identify an effector protein that can be potentially used as a therapeutic target in SCA1, we examined candidate proteins identified from our previous physical interaction or genetic modifier studies (Fernandez-Funez et al., 2000; Lim et al., 2006).”
BackgroundMethodSelf-citationIshitani, T., Ninomiya-Tsuji, J., Nagai, S.-I., Nishita, M., Meneghini, M., Barker, N., Waterman, M., Bowerman, B., Clevers, H., Shibuya, H., et al. (1999) · Nature · doi:10.1038/21674 · Cited by 624 · cited 1× · see citing works
“Across species, NLK proteins function as important regulators of cell growth, patterning, and death by controlling diverse signaling pathways, including Wnt and Notch pathways (Ishitani et al., 1999; Meneghini et al., 1999; Rocheleau et al., 1999; Verheyen et al., 2001; Rottinger et al., 2006).”
Ross, C. A. (2002) · Neuron · doi:10.1016/s0896-6273(02)00872-3 · Cited by 500 · cited 2× · see citing works
“This family of diseases includes Huntington disease, spinal and bulbar muscular atrophy, dentatorubropallidoluysian atrophy, and six autosomal dominant spinocerebellar ataxias (SCA1, 2, 3, 6, 7, and 17) (Ross, 2002).”
BackgroundPolyglutamine expansion down-regulates specific neuronal genes before pathologic changes in SCA1
Lin, X., Antalffy, B., Kang, D., Orr, H. T., & Zoghbi, H. Y. (2000) · Nature Neuroscience · doi:10.1038/72101 · Cited by 374 · cited 2× · see citing works
“Because alterations in gene expression is the earliest pathological finding in SCA1 disease (Lin et al., 2000; Serra et al., 2004; Cvetanovic et al., 2007, 2011; Crespo-Barreto et al., 2010; Fryer et al., 2011) and the CIC family proteins play a key role in modulating ATXN1 functions and SCA1…”
BackgroundSelf-citationWatase, K., Weeber, E. J., Xu, B., Antalffy, B., Yuva-Paylor, L., Hashimoto, K., Kano, M., Atkinson, R., Sun, Y., Armstrong, D. L., et al. (2002) · Neuron · doi:10.1016/s0896-6273(02)00733-x · Cited by 359 · cited 2× · see citing works
“Immunofluorescence staining of cerebellar sections and indirect quantitative analysis of Purkinje cell dendritic arborization were performed as described previously (Watase et al., 2002; Jafar-Nejad et al., 2011).”
Self-citationRotation of photoreceptor clusters in the developing drosophila eye requires the nemo gene
Choi, K.-W., & Benzer, S. (1994) · Cell · doi:10.1016/0092-8674(94)90579-7 · Cited by 339 · cited 1× · see citing works
“NLK is an evolutionarily conserved serine/ threonine protein kinase (Choi and Benzer, 1994; Banfi et al., 1996; Brott et al., 1998; Meneghini et al., 1999).”
BackgroundATAXIN-1 Interacts with the Repressor Capicua in Its Native Complex to Cause SCA1 Neuropathology
Lam, Y. C., Bowman, A. B., Jafar-Nejad, P., Lim, J., Richman, R., Fryer, J. D., Hyun, E. D., Duvick, L. A., Orr, H. T., Botas, J., et al. (2006) · Cell · doi:10.1016/j.cell.2006.11.038 · Cited by 326 · cited 21× · see citing works
“Our cell culture-based luciferase assay indicates that NLK can affect the transcriptional activity of the ATXN1/CIC protein complex (Fig.”
InfluentialSelf-citationOpposing effects of polyglutamine expansion on native protein complexes contribute to SCA1
Lim, J., Crespo-Barreto, J., Jafar-Nejad, P., Bowman, A. B., Richman, R., Hill, D. E., Orr, H. T., & Zoghbi, H. Y. (2008) · Nature · doi:10.1038/nature06731 · Cited by 311 · cited 9× · see citing works
“Gel-filtration (sizing) chromatography was performed as described previously with slight modifications (Lam et al., 2006; Lim et al., 2008).”
InfluentialSelf-citationSerine 776 of Ataxin-1 Is Critical for Polyglutamine-Induced Disease in SCA1 Transgenic Mice
Emamian, E. S., Kaytor, M. D., Duvick, L. A., Zu, T., Tousey, S. K., Zoghbi, H. Y., Clark, H. B., & Orr, H. T. (2003) · Neuron · doi:10.1016/s0896-6273(03)00258-7 · Cited by 305 · cited 3× · see citing works
“The phosphorylation of S776 in ATXN1 is extensively studied and is known to be crucial for the initiation and progression of SCA1 (Emamian et al., 2003; Duvick et al., 2010).”
Self-citationMeneghini, M. D., Ishitani, T., Carter, J. C., Hisamoto, N., Ninomiya-Tsuji, J., Thorpe, C. J., Hamill, D. R., Matsumoto, K., & Bowerman, B. (1999) · Nature · doi:10.1038/21666 · Cited by 293 · cited 2× · see citing works
“NLK is an evolutionarily conserved serine/ threonine protein kinase (Choi and Benzer, 1994; Banfi et al., 1996; Brott et al., 1998; Meneghini et al., 1999).”
BackgroundRocheleau, C. E., Yasuda, J., Shin, T. H., Lin, R., Sawa, H., Okano, H., Priess, J. R., Davis, R. J., & Mello, C. C. (1999) · Cell · doi:10.1016/s0092-8674(00)80784-9 · Cited by 276 · cited 1× · see citing works
“Across species, NLK proteins function as important regulators of cell growth, patterning, and death by controlling diverse signaling pathways, including Wnt and Notch pathways (Ishitani et al., 1999; Meneghini et al., 1999; Rocheleau et al., 1999; Verheyen et al., 2001; Rottinger et al., 2006).”
BackgroundIshitani, T., Ninomiya-Tsuji, J., & Matsumoto, K. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.4.1379-1389.2003 · Cited by 212 · cited 1× · see citing works
“NLK-KN is a lysine to methionine substitution at residue 155 (K155M) and is defective for kinase activity (Ishitani et al., 2003; Ishitani et al., 2011).”
Banfi, S., Borsani, G., Rossi, E., Bernard, L., Guffanti, A., Rubboli, F., Marchitiello, A., Giglio, S., Coluccia, E., Zollo, M., et al. (1996) · Nature Genetics · doi:10.1038/ng0696-167 · Cited by 189 · cited 1× · see citing works
“NLK is an evolutionarily conserved serine/ threonine protein kinase (Choi and Benzer, 1994; Banfi et al., 1996; Brott et al., 1998; Meneghini et al., 1999).”
The pathogenic mechanisms of polyglutamine diseases and current therapeutic strategies
Bauer, P. O., & Nukina, N. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06302.x · Cited by 178 · cited 1× · see citing works
“…of polyglutamine disease proteins plays important roles in disease pathogenesis by affecting diverse aspects of pathogenicity, including proteolytic cleavage, induction of a toxic conformational change, nuclear transport, and gene transcription (Bauer and Nukina, 2009; Pennuto et al., 2009).”
BackgroundSerra, H. G., Byam, C. E., Lande, J. D., Tousey, S. K., Zoghbi, H. Y., & Orr, H. T. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh268 · Cited by 176 · cited 2× · see citing works
“Because alterations in gene expression is the earliest pathological finding in SCA1 disease (Lin et al., 2000; Serra et al., 2004; Cvetanovic et al., 2007, 2011; Crespo-Barreto et al., 2010; Fryer et al., 2011) and the CIC family proteins play a key role in modulating ATXN1 functions and SCA1…”
BackgroundSelf-citationExercise and Genetic Rescue of SCA1 via the Transcriptional Repressor Capicua
Fryer, J. D., Yu, P., Kang, H., Mandel-Brehm, C., Carter, A. N., Crespo-Barreto, J., Gao, Y., Flora, A., Shaw, C., Orr, H. T., et al. (2011) · Science · doi:10.1126/science.1212673 · Cited by 162 · cited 7× · see citing works
“Building on our studies of SCA1 and ATXN1, we found that neurodegeneration in SCA1 results from a gain of endogenous functions mediated by the polyglutamine-expanded mutant ATXN1, and from a concurrent partial loss of the beneficial functions of wild-type (WT) ATXN1 (Lim et al., 2008; CrespoBarreto et al., 2010; Fryer…”
BackgroundInfluentialSelf-citationDuvick, L., Barnes, J., Ebner, B., Agrawal, S., Andresen, M., Lim, J., Giesler, G. J., Zoghbi, H. Y., & Orr, H. T. (2010) · Neuron · doi:10.1016/j.neuron.2010.08.022 · Cited by 145 · cited 3× · see citing works
“The phosphorylation of S776 in ATXN1 is extensively studied and is known to be crucial for the initiation and progression of SCA1 (Emamian et al., 2003; Duvick et al., 2010).”
BackgroundMethodSelf-citationCrespo-Barreto, J., Fryer, J. D., Shaw, C. A., Orr, H. T., & Zoghbi, H. Y. (2010) · PLoS Genetics · doi:10.1371/journal.pgen.1001021 · Cited by 136 · cited 4× · see citing works
“, 2006) as well as in vivo in mice (Crespo-Barreto et al., 2010; Fryer et al., 2011).”
BackgroundMethodInfluentialSelf-citationNlk is a murine protein kinase related to Erk/MAP kinases and localized in the nucleus
Brott, B. K., Pinsky, B. A., & Erikson, R. L. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.3.963 · Cited by 130 · cited 2× · see citing works
“If this is the case, then NLK will phosphorylate ATXN1 at serine (S) or threonine (T) residues followed by proline (P) because it is an MAPK-like kinase (Brott et al., 1998) and therefore targets the (S/T-P) consensus motif for phosphorylation.”
BackgroundATXN1 Protein Family and CIC Regulate Extracellular Matrix Remodeling and Lung Alveolarization
Lee, Y., Fryer, J. D., Kang, H., Crespo-Barreto, J., Bowman, A. B., Gao, Y., Kahle, J. J., Hong, J. S., Kheradmand, F., Orr, H. T., et al. (2011) · Developmental Cell · doi:10.1016/j.devcel.2011.08.017 · Cited by 109 · see citing works
Self-citationCvetanović, M., Patel, J. M., Marti, H. H., Kini, A. R., & Opal, P. (2011) · Nature Medicine · doi:10.1038/nm.2494 · Cited by 96 · cited 2× · see citing works
“Because alterations in gene expression is the earliest pathological finding in SCA1 disease (Lin et al., 2000; Serra et al., 2004; Cvetanovic et al., 2007, 2011; Crespo-Barreto et al., 2010; Fryer et al., 2011) and the CIC family proteins play a key role in modulating ATXN1 functions and SCA1…”
BackgroundBowman, A. B., Lam, Y. C., Jafar-Nejad, P., Chen, H.-K., Richman, R., Samaco, R. C., Fryer, J. D., Kahle, J. J., Orr, H. T., & Zoghbi, H. Y. (2007) · Nature Genetics · doi:10.1038/ng1977 · Cited by 86 · cited 4× · see citing works
“Thus, complex for the pathogenesis of SCA1 (Lam et al., 2006; Bowman et al., 2007; Lim et al., 2008; Jafar-Nejad et al., 2011), we next investigated the effects of decreasing NLK protein level by 50% on the formation and maintenance of ATXN1 protein complexes.”
BackgroundResultInfluentialSelf-citationPost-translational modifications of expanded polyglutamine proteins: impact on neurotoxicity
Pennuto, M., Palazzolo, I., & Poletti, A. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddn412 · Cited by 82 · cited 1× · see citing works
“…of polyglutamine disease proteins plays important roles in disease pathogenesis by affecting diverse aspects of pathogenicity, including proteolytic cleavage, induction of a toxic conformational change, nuclear transport, and gene transcription (Bauer and Nukina, 2009; Pennuto et al., 2009).”
BackgroundJafar‐Nejad, P., Ward, C. S., Richman, R., Orr, H. T., & Zoghbi, H. Y. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1018748108 · Cited by 65 · cited 5× · see citing works
“Immunofluorescence staining of cerebellar sections and indirect quantitative analysis of Purkinje cell dendritic arborization were performed as described previously (Watase et al., 2002; Jafar-Nejad et al., 2011).”
MethodInfluentialSelf-citationRöttinger, E., Croce, J., Lhomond, G., Besnardeau, L., Gache, C., & Lepage, T. (2006) · Development · doi:10.1242/dev.02603 · Cited by 54 · cited 1× · see citing works
“Across species, NLK proteins function as important regulators of cell growth, patterning, and death by controlling diverse signaling pathways, including Wnt and Notch pathways (Ishitani et al., 1999; Meneghini et al., 1999; Rocheleau et al., 1999; Verheyen et al., 2001; Rottinger et al., 2006).”
BackgroundThe role of LANP and ataxin 1 in E4F‐mediated transcriptional repression
Cvetanovic, M., Rooney, R. J., Garcia, J. J., Toporovskaya, N., Zoghbi, H. Y., & Opal, P. (2007) · The EMBO Reports · doi:10.1038/sj.embor.7400983 · Cited by 52 · cited 2× · see citing works
“Because alterations in gene expression is the earliest pathological finding in SCA1 disease (Lin et al., 2000; Serra et al., 2004; Cvetanovic et al., 2007, 2011; Crespo-Barreto et al., 2010; Fryer et al., 2011) and the CIC family proteins play a key role in modulating ATXN1 functions and SCA1…”
BackgroundSelf-citationThe tissue polarity gene nemo carries out multiple roles in patterning during Drosophila development
Verheyen, E. M., Mirkovic, I., MacLean, S. J., Langmann, C., Andrews, B. C., & MacKinnon, C. (2001) · Mechanisms of Development · doi:10.1016/s0925-4773(00)00574-8 · Cited by 45 · cited 1× · see citing works
“Across species, NLK proteins function as important regulators of cell growth, patterning, and death by controlling diverse signaling pathways, including Wnt and Notch pathways (Ishitani et al., 1999; Meneghini et al., 1999; Rocheleau et al., 1999; Verheyen et al., 2001; Rottinger et al., 2006).”
BackgroundHomodimerization of Nemo-like kinase is essential for activation and nuclear localization
Ishitani, S., Inaba, K., Matsumoto, K., & Ishitani, T. (2010) · Molecular Biology of the Cell · doi:10.1091/mbc.e10-07-0605 · Cited by 35 · cited 1× · see citing works
“NLK-KN is a lysine to methionine substitution at residue 155 (K155M) and is defective for kinase activity (Ishitani et al., 2003; Ishitani et al., 2011).”
BackgroundIdentification of a novel phosphorylation site in ataxin-1
Vierra‐Green, C., Orr, H. T., Zoghbi, H. Y., & Ferrington, D. A. (2004) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2004.10.012 · Cited by 18 · cited 2× · see citing works
“One of these sites is serine 239 (S239), which was identified as an in vivo ATXN1 phosphorylation site in multiple tissues, including brain, by mass spectrometry analysis (Vierra-Green et al., 2005; Huttlin et al., 2010).”
BackgroundSelf-citation
Flagged first, then by citations
Cited by
Sorted by citations
Post-translational modifications: Regulators of neurodegenerative proteinopathies
Gupta, R. V., Sahu, M., Srivastava, D., Tiwari, S., Ambasta, R. K., & Kumar, P. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101336 · Cited by 124 · see citing works
Pathogenic mechanisms underlying spinocerebellar ataxia type 1
Tejwani, L., & Lim, J. (2020) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03520-z · Cited by 38 · see citing works
Self-citationGenes and Genetic Testing in Hereditary Ataxias
Sandford, E., & Burmeister, M. (2014) · Genes · doi:10.3390/genes5030586 · Cited by 37 · see citing works
“Nemo-like kinase (NLK) has been shown to interact with ATXN1 transcriptional complex, and decreased expression of NLK positively modulates the phenotype in SCA1 models, providing another biological target for future treatments [82].”
BackgroundLongitudinal single-cell transcriptional dynamics throughout neurodegeneration in SCA1
Tejwani, L., Ravindra, N. G., Lee, C., Cheng, Y., Nguyen, B., Luttik, K. P., Ni, L., Zhang, S., Morrison, L. M., Gionco, J. T., et al. (2023) · Neuron · doi:10.1016/j.neuron.2023.10.039 · Cited by 36 · see citing works
Self-citationRole of water in protein folding, oligomerization, amyloidosis and miniprotein
Vajda, T., & Perczel, A. (2014) · Journal of Peptide Science · doi:10.1002/psc.2671 · Cited by 33 · see citing works
Ju, H., Kokubu, H., & Lim, J. (2014) · Molecular Neurobiology · doi:10.1007/s12035-014-8703-z · Cited by 28 · see citing works
“The functional significance of S239 phosphorylation is largely unknown, but a recent study suggests its potential significance in ATXN1 function and SCA1 pathogenesis [35].”
Self-citationUbe3a/E6AP is involved in a subset of MeCP2 functions
Kim, S., Chahrour, M. H., Ben‐Shachar, S., & Lim, J. (2013) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2013.06.036 · Cited by 23 · see citing works
Self-citationCortés, C. J., & Spada, A. R. L. (2018) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-71779-1_5 · Cited by 23 · see citing works
Nemo-like kinase is a novel regulator of spinal and bulbar muscular atrophy
Todd, T. W., Kokubu, H., Miranda, H. C., Cortes, C. J., La Spada, A. R., & Lim, J. (2015) · eLife · doi:10.7554/elife.08493 · Cited by 21 · see citing works
“, 2013), UAS-NLK-KN (Ju et al., 2013), nmo (Verheyen et al.”
BackgroundMethodInfluentialSelf-citationNemo-Like Kinase in Development and Diseases: Insights from Mouse Studies
Daams, R., & Massoumi, R. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21239203 · Cited by 21 · see citing works
“Using the NLK heterozygous SCA1 knock-in model, it was found that NLK haploinsufficiency can rescue SCA1 cerebellar pathology and motor phenotypes [50].”
BackgroundNemo-like kinase reduces mutant huntingtin levels and mitigates Huntington’s disease
Jiang, M., Zhang, X., Liu, H., LeBron, J., Alexandris, A., Peng, Q., Gu, H., Yang, F., Li, Y., Wang, R., et al. (2020) · Human Molecular Genetics · doi:10.1093/hmg/ddaa061 · Cited by 15 · see citing works
“(SMBA), respectively, and genetic reduction of NLK levels modulates behavioral deficits and neuropathology in both SCA1 and SBMA models (31,32).”
BackgroundSelf-citationTejwani, L., Jung, Y., Kokubu, H., Sowmithra, S., Ni, L., Lee, C., Sanders, B., Lee, P. J., Xiang, Y., Luttik, K., et al. (2023) · Journal of Clinical Investigation · doi:10.1172/jci138207 · Cited by 17 · see citing works
“To test this, 156 we crossed two independent Nlk gene trap loss-of-function mouse lines (NlkXN619/+ and NlkRRJ297/+) 157 (7, 8), collectively referred to here as Nlk+/-, with transgenic mice expressing a fALS-causing 158 mutant hTARDBPA315T under the control of a Prp promoter (28), referred to here as Prp-TDPA315T/+.”
BackgroundMethodInfluentialSelf-citationModulation of ATXN1 S776 phosphorylation reveals the importance of allele-specific targeting in SCA1
Nitschke, L., Coffin, S. L., Xhako, E., El-Najjar, D. B., Orengo, J., Alcala, E., Dai, Y.-W., Wan, Y., Liu, Z.-D., Orr, H., et al. (2021) · JCI Insight · doi:10.1172/jci.insight.144955 · Cited by 16 · see citing works
“In accordance with previous findings (21), we found that the thickness of the cerebellar molec-”
ResultSelf-citationRoles of Post-translational Modifications in Spinocerebellar Ataxias
Wan, L., Xu, K., Chen, Z., Tang, B., & Jiang, H. F. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00290 · Cited by 16 · see citing works
“One study suggested that ATXN1 could be phosphorylated at S239 by Nemo-like kinase (NLK), an ATXN1 interactor that modulates the toxicity of SCA1; this hypothesis is supported by NLK overexpression in a Drosophila model, which increased ATXN1 disease-related phenotypes (Ju et al., 2013).”
BackgroundLee, W., Lavery, L. A., Rousseaux, M. W. C., Rutledge, E. B., Jang, Y., Wan, Y., Wu, S., Kim, W., Al‐Ramahi, I., Rath, S., et al. (2021) · The EMBO Journal · doi:10.15252/embj.2020106106 · Cited by 17 · see citing works
“For example, reducing Msk1 or Nlk rescues cerebellar phenotypes, and pharmacological inhibition of PAKs decreases cerebellar Atxn1 levels in SCA1 mice (Ju et al, 2013; Park et al, 2013; Bondar et al, 2018).”
Self-citationLuttik, K., Tejwani, L., Ju, H., Driessen, T., Smeets, C., Edamakanti, C. R., Khan, A., Yun, J., Opal, P., & Lim, J. (2022) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.2208513119 · Cited by 16 · see citing works
Self-citationX-gal Staining on Adult Mouse Brain Sections
Kokubu, H., & Lim, J. (2014) · BIO-PROTOCOL · doi:10.21769/bioprotoc.1064 · Cited by 14 · see citing works
“This protocol was adapted from the previously published paper: Ju et al. (2013).”
MethodSelf-citationFruitful research: drug target discovery for neurodegenerative diseases in Drosophila
Konsolaki, M. (2013) · Expert Opinion on Drug Discovery · doi:10.1517/17460441.2013.849691 · Cited by 13 · see citing works
“Among these, the Nemolike kinase interacts with both wild-type and expanded Atxn1 and can modulate Atxn1-induced phenotypes [67].”
BackgroundIdentifying Disease Signatures in the Spinocerebellar Ataxia Type 1 Mouse Cortex
Luttik, K. P., Olmos, V., Owens, A., Khan, A., Yun, J., Driessen, T. M., & Lim, J. (2022) · Cells · doi:10.3390/cells11172632 · Cited by 9 · see citing works
Self-citationGrass carp (Ctenopharyngodon idella) NLK2 inhibits IFN I response through blocking MAVS-IRF3 axis
Yu, T., Zeng, Q., Mao, H., Liu, Y., Zhang, H., Wang, S., Hu, C., & Xu, X. (2022) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2022.10.002 · Cited by 5 · see citing works
Nemo promotes Notch-mediated lateral inhibition downstream of proneural factors
Fernandes, V. M., Panchapakesan, S. S. S., Braid, L. R., & Verheyen, E. M. (2014) · Developmental Biology · doi:10.1016/j.ydbio.2014.05.013 · Cited by 4 · see citing works
Exploring the Role of Posttranslational Modifications in Spinal and Bulbar Muscular Atrophy
Gogia, N., Ni, L., Olmos, V., Haidery, F., Luttik, K. P., & Lim, J. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.931301 · Cited by 5 · see citing works
“Aberrant PTMs of specific proteins or dysregulation of PTM homeostasis have been implicated in modulating pathophysiology of polyQ diseases, such as SCA1 (Ju et al., 2013; Ju et al., 2014; Kang et al., 2015), HD (Martin et al.”
BackgroundSelf-citationDominantly Inherited Spinocerebellar Syndromes
Maricich, S. M., & Zoghbi, H. Y. (2014) · Elsevier eBooks · doi:10.1016/b978-0-12-417044-5.00050-0 · Cited by 3 · see citing works
Self-citationNemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS
Bekier, M. E., Pinarbasi, E., Krishnan, G., Mesojedec, J. J., Hurley, M., Harikumar Sheela, H., Collins, C. A., Ghaffari, L., de Majo, M., Ullian, E. M., et al. (2025) · Journal of Clinical Investigation · doi:10.1172/jci188138 · Cited by 2 · see citing works
Ramani, B. (2015) · Deep Blue (University of Michigan)
Dong, T., Kokubu, H., Driessen, T. M., Tejwani, L., & Lim, J. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/358010
Self-citationIshitani, T., & Ishitani, S. (2016) · Springer eBooks · doi:10.1007/978-1-4614-6438-9_101750-1
Ishitani, T., & Ishitani, S. (2017) · Springer eBooks · doi:10.1007/978-3-319-67199-4_101750
Molecular mechanisms and clinical implications of Wnt pathway inhibition
Wang, R., & Wang, P. (2025) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2025.152806
Transcriptional kinases drive gene expression network plasticity
Lowe, D. D., & Shilatifard, A. (2026) · Molecular Cell · doi:10.1016/j.molcel.2026.07.035
Microglia regulate brain progranulin levels through the endocytosis/lysosomal pathway
Dong, T., Tejwani, L., Jung, Y., Kokubu, H., Luttik, K., Driessen, T. M., & Lim, J. (2021) · JCI Insight · doi:10.1172/jci.insight.136147 · Cited by 13 · see citing works
“As previously reported (48), a small amount of residual Nlk remained (~10%) in Nlk–/– animals due to limitations of gene trap technology.”
BackgroundMethodSelf-citation
- Authors
- Ju, H., Kokubu, H., Todd, T. W., Kahle, J. J., Kim, S., Richman, R., Chirala, K., Orr, H. T., Zoghbi, H. Y., & Lim, J.
- Affiliations
- Yale University (US)
- Baylor College of Medicine (US)
- University of Minnesota (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2013-05-29
- Volume
- 33
- Issue
- 22
- Pages
- 9328-9336
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3710458
- OpenAlex
- W2025554299
- Semantic Scholar
- 032908dd4576e7e54c77b9098b4fb8c6bd5b67d6
- Cited by
- 31
- References
- 35
- Citations by year
- 2026: 1 · 2025: 2 · 2023: 2 · 2022: 4 · 2021: 4 · 2020: 3 · 2018: 3 · 2017: 1 · 2016: 1 · 2015: 2 · 2014: 6 · 2013: 2
- FWCI
- 1.60
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (submittedVersion)
- PubMed Central (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Alfred P. Sloan Foundation
- National Ataxia Foundation
- Yale University
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R00 NS064146, R01 NS027699, NS027699, K99NS064146, R37 NS027699, NS064146)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- spinocerebellar ataxia type 1, Nemo-like kinase, polyglutamine diseases, CAG repeat expansion, kinase activity, neurodegeneration, Drosophila model, knock-in mice, serine/threonine kinase
- MeSH terms
- Ataxins, Ataxin-1, Animals, Behavior, Animal, Brain, Cerebellum, Chromatography, Gel, Drosophila melanogaster, Female, Humans, Mice, Inbred C57BL, Mice, Transgenic, Nerve Tissue Proteins, Nuclear Proteins, Peptides, Phosphorylation, Blotting, Western, Gene Expression, Protein Serine-Threonine Kinases, Heredodegenerative Disorders, Nervous System, Spinocerebellar Ataxias, Mitogen-Activated Protein Kinases, Animals, Genetically Modified, Immunoprecipitation, Mice, HEK293 Cells
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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