Reduction of nemo-like kinase increases lysosome biogenesis and ameliorates TDP-43–related neurodegeneration
Open accessPublished version of a preprint
Abstract
Protein aggregation is a hallmark of many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Although mutations in TARDBP, encoding transactive response DNA-binding protein 43 kDa (TDP-43), account for less than 1% of all ALS cases, TDP-43-positive aggregates are present in nearly all ALS patients, including patients with sporadic ALS (sALS) or carrying other familial ALS-causing (fALS-causing) mutations. Interestingly, TDP-43 inclusions are also present in subsets of patients with frontotemporal dementia, Alzheimer's disease, and Parkinson's disease; therefore, methods of activating intracellular protein quality control machinery capable of clearing toxic cytoplasmic TDP-43 species may alleviate disease-related phenotypes. Here, we identify a function of nemo-like kinase (Nlk) as a negative regulator of lysosome biogenesis. Genetic or pharmacological reduction of Nlk increased lysosome formation and improved clearance of aggregated TDP-43. Furthermore, Nlk reduction ameliorated pathological, behavioral, and life span deficits in 2 distinct mouse models of TDP-43 proteinopathy. Because many toxic proteins can be cleared through the autophagy/lysosome pathway, targeted reduction of Nlk represents a potential approach to therapy development for multiple neurodegenerative disorders.
AI snapshot
Written from the paper’s full text.
TL;DR
Nemo-like kinase (Nlk) is identified as a negative regulator of lysosome biogenesis; reducing Nlk increases lysosomal gene expression and clearance of aggregated TDP-43. Genetic or antisense oligonucleotide–mediated Nlk reduction ameliorated pathology, behavior, and survival in two TDP-43 mouse models.
Key findings
- Nlk knockout in N2a cells increased lysosome number and proteolytic activity, promoted CLEAR-network transcription, and increased LC3-II/LC3-I with decreased p62; NLK+/– human iPSC-derived motor neurons expressed higher CTSA, CTSD, LAMP1, and LAMP2.
- Nlk overexpression reduced nuclear Tfeb in a kinase activity–dependent manner; MG132 restored nuclear Tfeb, indicating Nlk destabilizes nuclear Tfeb via the nuclear proteasome without altering mTOR targets or Tfeb S122/S142 phosphorylation.
- Nlk reduction decreased full-length and truncated TDP-43 in cells and decreased insoluble TDP-43 fractions in mouse spinal cord without affecting soluble TDP-43; Nlk did not physically interact with TDP-43.
- In Prp-TDPA315T/+ mice, 50% genetic Nlk reduction increased median survival by about 20% in males and females and increased motor neuron Lamp1-positive lysosomes; in Thy1-TDPTg/Tg mice, P1 10 μg Nlk ASO reduced Nlk mRNA by 90% in cortex and 75% in spinal cord at P19 and increased median life span by 21%.
Methods
- Used N2a and NSC-34 cells, CRISPR/Cas9 Nlk-knockout N2a clones, RNA-Seq/GSEA/ToppCluster/IPA, luciferase reporters, Western blotting, subcellular fractionation, LysoTracker and DQ BSA assays, and CRISPR-mutated NLK+/– hiPSC-derived motor neurons.
- Used two Nlk loss-of-function mouse lines crossed with Prp-TDPA315T/+ mice, plus Thy1-TDPTg/Tg mice treated with P1 intracerebroventricular Nlk ASO; assessed survival, motor behavior, immunostaining, and detergent-fractionated TDP-43.
- Statistical analysis used two-tailed unpaired Student’s t test or one-way ANOVA with multiple comparisons; P < 0.05 was significant.
Limitations
- The paper states that genetic and pharmacological Nlk reduction occurred prenatally or at P1, so benefits may reflect altered disease onset and/or progression; it calls for future comparison across disease stages and for determining the effective therapeutic time window.
- The paper notes that survival improvement was only around 20% and that the TDP-43 mouse models may have premature lethality driven by gastrointestinal or other non-neurological transgene effects, requiring models where neurodegeneration primarily drives lethality.
- The paper states that comprehensive lysosomal health/function beyond immunostaining for a single lysosomal membrane marker is needed; the text also makes evident that evidence is from rodent models and cell systems, with no human clinical data.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
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Cites
Statistics
Claims the paper makes
15 of 16 cited sources checked · 10 supported · 0 flagged · accuracy not yet measured
- Premisecitation
Mice with postnatal whole-body conditional ablation of Nlk are grossly normal.
“and mice with postnatal whole-body conditional ablation of Nlk are grossly normal (57)”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [57] source
The Results (‘Decreased expression of Nlk reduces Pgrn levels in vivo’; page unavailable) describe tamoxifen-induced conditional deletion of Nlk in all cell types beginning at six weeks of age. They report reduced cortical Nlk and Pgrn levels, but do not say that these mice were grossly normal. The normal behavioral findings elsewhere in the Results concern Nlk heterozygotes, not the conditionally ablated mice. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Findingown data
Nlk reduction improves survival in 2 independent TDP-43 animal models.
“The therapeutic benefits of Nlk reduction on motor behavior, neurodegeneration and its associated astrogliosis, and survival of 2 independent TDP-43 animal models”
Quote in the paperSubstantial claim - Findingown data
Nlk reduction improves motor behavior in 2 independent TDP-43 animal models.
“The therapeutic benefits of Nlk reduction on motor behavior, neurodegeneration and its associated astrogliosis, and survival of 2 independent TDP-43 animal models”
Quote in the paperSubstantial claim - Findingnone given
Pathological rescue of TDP-43-related neurodegeneration and gliosis upon Nlk reduction was to near nontransgenic control levels.
“although the pathological rescue of TDP-43–related neurodegeneration and gliosis upon Nlk reduction was to near nontransgenic control levels”
Quote in the paperSubstantial claim - Findingown data
The observed improvement in survival in both TDP-43 transgenic mouse models was only around 20%.
“the observed improvement in survival in both TDP-43 transgenic mouse models was only around 20%”
Quote in the paperSubstantial claim
- Interpretationcitation
The aggressive disease progression in these models contributes to premature lethality prior to robust lysosomal dysfunction that may eventually be induced by aberrant TDP-43 aggregation.
“likely due to the aggressive disease progression in these models that contributes to premature lethality prior to robust lysosomal dysfunction that may eventually be induced by aberrant TDP-43 aggregation (50).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [50] source
- Rests on an assumption: The animals used in the present study have not been reported to display overt impairments in autophagy/lysosome function.
- Interpretationown data
Promoting lysosomal biogenesis in animal models of TDP-43 proteinopathy via the reduction of Nlk appears to have a beneficial impact on nearly all aspects of disease pathology.
“promoting lysosomal biogenesis in animal models of TDP-43 proteinopathy via the reduction of Nlk appears to have a beneficial impact on nearly all aspects of disease pathology, as demonstrated in the in vivo studies presented here.”
Quote in the paperSubstantial claim - Interpretationreasoning
The mechanism of therapeutic benefit by Nlk reduction described here is an indirect one likely mediated through increased lysosomal clearance of aggregated TDP-43.
“Rather than a direct effect of altering phosphorylation of the disease-causing protein, the mechanism of therapeutic benefit by Nlk reduction described here is an indirect one likely mediated through increased lysosomal clearance of aggregated TDP-43”
Quote in the paperSubstantial claim- Rests on an assumption: There is no physical interaction between NLK and TDP-43 (or no evidence for it).
- Rests on an assumption: NLK has not been previously identified in genetic screens of modulators of TDP-43 toxicity.
- Interpretationnone given
The present study is one of the first to generate and validate the therapeutic benefit of ASOs targeting a disease modifier (and not the disease-causing gene itself) in rodent models of a neurodegenerative disease.
“To our knowledge, the present study is one of the first to generate and validate the therapeutic benefit of ASOs targeting a disease modifier (and not the disease-causing gene itself) in rodent models of a neurodegenerative disease.”
Quote in the paperNot a substantial claim - Premisereasoning
The utility of ASO approaches is restricted to subsets of patients that carry specific, rare mutations in the gene of interest.
“While these approaches have proven to be extremely effective in preclinical genetic models of these disorders, the utility of such approaches is restricted to subsets of patients that carry specific, rare mutations in the gene of interest.”
Quote in the paperSubstantial claim - Interpretationcitation
Targeted reduction of Nlk or its downstream effectors to increase ALP function is a potentially generalizable therapeutic strategy for several neurodegenerative disorders, beyond just ALS.
“we believe targeted reduction of Nlk or its downstream effectors to increase ALP function is a potentially generalizable therapeutic strategy for several neurodegenerative disorders, beyond just ALS.”
Quote in the paperSubstantial claim- Rests on an assumption: No known neurological condition in humans has been associated with a reduction of Nlk.
- Interpretationreasoning
Targeted reduction of a mutated protein is not possible in the vast majority of ALS patients with sporadic disease.
“therefore, targeted reduction of a mutated protein is not possible.”
Quote in the paperSubstantial claim- Rests on an assumption: In ALS, the vast majority of patients have a sporadic form of the disease in which a genetic etiology is not identifiable.
- Interpretationnone given
This study is the first to target a novel molecule that has not been implicated as a genetic risk factor for the disease being studied.
“Among these, we believe this study is the first to target a novel molecule that has not been implicated as a genetic risk factor for the disease being studied.”
Quote in the paperNot a substantial claim
- Classified as probably not a substantial claim. 15
- May combine two claims. 10
- The quote only partly states this claim. 2
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationNLK 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”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [7] source
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 measured - cites [8] source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationPhosphorylation of AR and ataxin-1 contributes to pathogenicity.
“and that phosphorylation of these proteins contributes to pathogenicity (7, 8).”
Quote in the paperNot a substantial claim2 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductcitationCell lines were routinely tested for mycoplasma contamination by PCR and positive samples were discarded.
“Cells were routinely tested for mycoplasma contamination by PCR as previously described (58) using primers for-GGCGAATGGGTGAGTAACACG and rev-CGGATAACGCTTGCGACCTATG. Any mycoplasma-positive samples were immediately discarded.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [58] source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationASOs can specifically alter levels and/or processing of a variety of proteins involved in neurodegenerative diseases, most of which have been the disease-causing protein itself.
“Due to the precision afforded by complementary binding of an ASO to its target transcript of interest, ASOs have emerged as an invaluable tool in specifically altering levels and/or processing of a variety of proteins involved in neurodegenerative diseases, most of which have been the disease-causing protein itself (38, 51–54).”
Quote in the paperNot a substantial claim5 of 5 sources checked- cites [38] source
- cites [51] source
- cites [52] source
- cites [53] source
- cites [54] source
The paper reports that sequence-specific ASO7 lowered the disease-causing ATXN2 protein in SCA2 models and discusses ASO approaches for other neurodegenerative diseases. It does not establish that most ASO targets across those diseases are the disease-causing proteins, or document altered protein processing. The supplied passages are labeled Abstract and have no page numbers. (LLM, conf=0.83)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationMice with partial genetic reduction of Nlk display no pathological (neurodegenerative or inflammatory), survival, or cognitive changes up to 52 weeks.
“mice with partial genetic reduction of Nlk display no pathological (neurodegenerative or inflammatory), survival, or cognitive changes up to 52 weeks (57)”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [57] source
The Results sections report no significant microglial changes or elevated-plus-maze behavioral phenotype in Nlk+/– mice alone at one year, compared with wild-type controls. They do not establish unchanged survival or explicitly report normal cognitive performance for Nlk+/– mice alone; the reported Morris water maze impairment concerns Nlk+/– Grn+/– mice. Thus, the claim is broader than the findings in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationPathological TDP-43 aggregation and premature polyadenylation and loss of stathmin-2 are pathologies commonly observed across sALS and fALS.
“alternative approaches that mitigate pathologies commonly observed across sALS and fALS, such as pathological TDP-43 aggregation (39) or premature polyadenylation and loss of stathmin-2, a key regulator of microtubule dynamics in motor neurons (55, 56), are highly desirable.”
Quote in the paperSubstantial claim3 of 3 sources checked- cites [39] source
- cites [55] source
- cites [56] source
The Results sections on postmortem ALS spinal cord and mutant TDP-43 motor neurons report reduced STMN2 in sporadic cases and in patient-derived motor neurons. The paper links STMN2 loss to cryptic-exon splicing, but the passages do not establish premature polyadenylation. Its Discussion also notes that FUS-mutant patients do not display TDP-43 pathology, so the claim's broad framing across sporadic and familial ALS needs qualification. TDP-43 aggregation is separately cited to reference 39 in the citing sentence. (LLM, conf=0.87)
Experimental — accuracy not yet measured
May combine two claims.
Findingown dataNlk reduction reduces neurodegeneration and associated astrogliosis in 2 independent TDP-43 animal models.
“The therapeutic benefits of Nlk reduction on motor behavior, neurodegeneration and its associated astrogliosis, and survival of 2 independent TDP-43 animal models”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataNlk reduction provides proof-of-principle evidence for this approach in TDP-43 proteinopathies, both when TARDBP mutations are present and when TARDBP mutations are not present but TDP-43 aggregation occurs.
“provide strong proof-of-principle evidence for this approach in TDP-43 proteinopathies, both in instances in which TARDBP mutations are present (a subset of ALS patients) and when TARDBP mutations are not present but TDP-43 aggregation occurs.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductnone givenMicroscope acquisition parameters were identical for all images in the LysoTracker live-cell imaging experiments.
“Cells were maintained in Live Cell Imaging Solution (Invitrogen) at 37°C in 5% CO2 during image acquisition, and microscope acquisition parameters for all images were identical.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe experimenter was blind to animal genotype and ASO treatment during behavioral assessment.
“The experimenter was blind to animal genotype and ASO treatment.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductnone givenAt least 3 animals were examined for all histological analyses, with at least three to nine 30 μm sections from comparable brain or spinal cord regions quantified per animal.
“For all histological analyses, at least 3 animals were examined, with at least three to nine 30 μm sections from comparable brain/spinal cord regions quantified per animal.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe experimenter was blind to animal genotype and ASO treatment during image acquisition and quantification of histological analyses.
“The experimenter was blind to animal genotype and ASO treatment during image acquisition and quantification.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductnone givenLysosome number per cell was blindly quantified and normalized by cell area in LysoTracker imaging.
“Lysosome number per cell was blindly quantified and normalized by cell area.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. The quote only partly states this claim.
Study design and conductown dataEqual protein amounts were loaded for SDS-PAGE and Western blot analysis.
“Total protein concentrations of isolated protein lysates were quantified using the BCA Protein Assay Kit (Thermo Fisher), and equal protein amounts were boiled at 95°C for 10 minutes, loaded, and analyzed by SDS-PAGE.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenMicroscope acquisition parameters were identical for all images in the DQ BSA live-cell imaging experiments.
“Microscope acquisition parameters for all images were identical.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenRNA integrity was assessed with RIN values before sequencing to ensure high RNA integrity.
“RNA integrity was measured using an Agilent Bioanalyzer 2100 (Agilent Technologies), and RIN values were assessed to ensure high RNA integrity before sequencing.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenAll luciferase reporter experiments were repeated in triplicate and performed at least 3 times.
“All experiments were repeated in triplicate and performed at least 3 times.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. The quote only partly states this claim.
Study design and conductnone givenLysosome number per cell was blindly quantified in DQ BSA assays.
“Lysosome number per cell was blindly quantified.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenStitched images were deidentified and randomized before quantification of NeuN-positive layer V cortical neurons.
“Briefly, following acquisition and stitching of a 3 × 3 tiled array of ×20 images, stitched images were deidentified and randomized.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
There is no physical interaction between NLK and TDP-43 (or no evidence for it).
“as there is no evidence for a physical interaction between NLK and TDP-43.”
The paper relies on this without support.
In ALS, the vast majority of patients have a sporadic form of the disease in which a genetic etiology is not identifiable.
“In the case of ALS, the vast majority of patients have a sporadic form of the disease in which a genetic etiology is not identifiable”
The paper relies on this without support.
No known neurological condition in humans has been associated with a reduction of Nlk.
“Because no known neurological condition in humans has been associated with a reduction of Nlk”
The paper relies on this without support.
The animals used in the present study have not been reported to display overt impairments in autophagy/lysosome function.
“the animals used in the present study have not been reported to display overt impairments in autophagy/lysosome function”
The paper relies on this without support.
NLK has not been previously identified in genetic screens of modulators of TDP-43 toxicity.
“NLK has not been previously identified in genetic screens of modulators of TDP-43 toxicity.”
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 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 [16]
The Results section reports that Nlk reduction improved survival and disease phenotypes in TDP-43 mouse models. The Introduction reports earlier alleviation of disease phenotypes in SCA1 and SBMA animal models. Our copy does not report a Drosophila ALS model, so that part of the claim is unsupported by this source. (LLM, conf=0.84)
Experimental — accuracy not yet measuredNLK 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 [16]
Nlk 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 [16]
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Boillée, S., Yamanaka, K., Lobsiger, C. S., Copeland, N. G., Jenkins, N. A., Kassiotis, G., Kollias, G., & Cleveland, D. W. (2006) · Science · doi:10.1126/science.1123511 · Cited by 1,623 · cited 1× · see citing works
“In addition to increasing overall survival, disease onset, which was defined as the first time point in which weight gain was no longer observed (35, 36), was delayed in male mice with a 50% genetic reduction of Nlk (Supplemental Figure 7C).”
BackgroundRoczniak-Ferguson, A., Petit, C. S. V., Froehlich, F., Qian, S., Ky, J., Angarola, B. L., Walther, T. C., & Ferguson, S. M. (2012) · Science Signaling · doi:10.1126/scisignal.2002790 · Cited by 1,358 · cited 1× · see citing works
“Phosphorylation of Tfeb at specific residues by various kinases, the best documented being mTOR, has been ascribed to be a major mechanism that governs subcellular localization and activity of Tfeb (18, 21–24).”
BackgroundFinkel, R. S., Chiriboga, C. A., Vajsar, J., Day, J., Montes, J., Vivo, D. C. D., Yamashita, M., Rigo, F., Hung, G., Schneider, E., et al. (2016) · The Lancet · doi:10.1016/s0140-6736(16)31408-8 · Cited by 1,019 · cited 1× · see citing works
“spinal muscular atrophy (36) and Huntington’s disease (37).”
BackgroundSelf-citationExome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways
Cirulli, E. T., Lasseigne, B. N., Petrovski, S., Sapp, P. C., Dion, P. A., Leblond, C. S., Couthouis, J., Lu, Y.-F., Wang, Q., Krueger, B. J., et al. (2015) · Science · doi:10.1126/science.aaa3650 · Cited by 966 · cited 1× · see citing works
“Although human genetics studies have revealed ALS-causing mutations in numerous genes that converge on the ALP (48, 49), the animals used in the present study have not been reported to display overt impairments in autophagy/lysosome function, likely due to the aggressive disease progression in…”
TDP‐43 immunoreactivity in hippocampal sclerosis and Alzheimer's disease
Amador‐Ortiz, C., Lin, W., Ahmed, Z., Personett, D., Davies, P., Duara, R., Graff‐Radford, N. R., Hutton, M. L., & Dickson, D. W. (2007) · Annals of Neurology · doi:10.1002/ana.21154 · Cited by 916 · cited 1× · see citing works
“…DNA-binding protein 43 kDa (TDP-43) are observed in approximately 97% of all patients, including patients with sporadic ALS (sALS) or familial ALS (fALS) (1–3), as well as in subsets of patients with frontotemporal dementia (FTD) (1, 3), Alzheimer’s disease (4), and Parkinson’s disease (5).”
BackgroundNapolitano, G., & Ballabio, A. (2016) · Journal of Cell Science · doi:10.1242/jcs.146365 · Cited by 836 · cited 1× · see citing works
“Several transcription factors have been reported to be involved in the transcriptional regulation of a large number of lysosomal genes, and among these, Tfeb has been described as a key master regulator of lysosome gene expression and function (14, 15, 17).”
BackgroundAntisense oligonucleotides: the next frontier for treatment of neurological disorders
Rinaldi, C., & Wood, M. J. A. (2018) · Nature Reviews Neurology · doi:10.1038/nrneurol.2017.148 · Cited by 788 · see citing works
Kordasiewicz, H. B., Stanek, L. M., Wancewicz, E. V., Mazur, C., McAlonis, M. M., Pytel, K. A., Artates, J. W., Weiss, A., Cheng, S. H., Shihabuddin, L. S., et al. (2012) · Neuron · doi:10.1016/j.neuron.2012.05.009 · Cited by 770 · cited 1× · see citing works
“been the disease-causing protein itself (33, 42-45).”
Targeting Huntingtin Expression in Patients with Huntington’s Disease
Tabrizi, S. J., Leavitt, B. R., Landwehrmeyer, G. B., Wild, E. J., Saft, C., Barker, R. A., Blair, N. F., Craufurd, D., Priller, J., Rickards, H., et al. (2019) · New England Journal of Medicine · doi:10.1056/nejmoa1900907 · Cited by 708 · cited 2× · see citing works
“Possibly due to the indirect nature of this interaction between NLK and TDP-43 through lysosome gene expression, NLK has not been previously identified in genetic screens of modulators of TDP-43 toxicity.”
BackgroundTDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration
Wegorzewska, I., Bell, S., Cairns, N. J., Miller, T. M., & Baloh, R. H. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0908767106 · Cited by 706 · cited 2× · 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/+.”
MethodWinton, M. J., Igaz, L. M., Wong, M. M., Kwong, L. K., Trojanowski, J. Q., & Lee, V. M. ‐. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m800342200 · Cited by 660 · cited 1× · see citing works
“distribution of TDP-43 to the nucleus (41).”
Gains or losses: molecular mechanisms of TDP43-mediated neurodegeneration
Lee, E. B., Lee, V. M.-Y., & Trojanowski, J. Q. (2012) · Nature Reviews Neuroscience · doi:10.1038/nrn3121 · Cited by 659 · cited 1× · see citing works
“and exacerbate loss of nuclear function pathogenic mechanisms (6), therefore, preventing the 27”
BackgroundALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair
Klim, J. R., Williams, L. A., Limone, F., Guerra San Juan, I., Davis-Dusenbery, B. N., Mordes, D. A., Burberry, A., Steinbaugh, M. J., Gamage, K. K., Kirchner, R., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-018-0300-4 · Cited by 653 · see citing works
Melamed, Z., López-Erauskin, J., Baughn, M. W., Zhang, O., Drenner, K., Sun, Y., Freyermuth, F., McMahon, M. A., Beccari, M. S., Artates, J. W., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-018-0293-z · Cited by 635 · see citing works
Self-citationTDP‐43 A315T mutation in familial motor neuron disease
Gitcho, M. A., Baloh, R. H., Chakraverty, S., Mayo, K., Norton, J. B., Levitch, D., Hatanpaa, K. J., White, C. L., Bigio, E. H., Caselli, R. J., et al. (2008) · Annals of Neurology · doi:10.1002/ana.21344 · Cited by 619 · cited 1× · see citing works
“Coexpression of TDP-43 WT or mutant TDP-43 A315T , a fALS-causing variant of TDP-43 (31), with Nlk in NSC-34 cells induced a kinase activity–dependent increase in total TDP-43 and a 35 kDa TDP species, both of which also increased with lysosome inhibitor bafilomycin A1 (BafA1) (Figure 3, A and B).”
BackgroundMiller, T. M., Pestronk, A., David, W., Rothstein, J., Simpson, E., Appel, S. H., Andres, P. L., Mahoney, K., Allred, P., Alexander, K., et al. (2013) · The Lancet Neurology · doi:10.1016/s1474-4422(13)70061-9 · Cited by 617 · see citing works
Neumann, M., Kwong, L. K., Lee, E. B., Kremmer, E., Flatley, A., Xu, Y., Forman, M. S., Troost, D., Kretzschmar, H. A., Trojanowski, J. Q., et al. (2009) · Acta Neuropathologica · doi:10.1007/s00401-008-0477-9 · Cited by 604 · cited 1× · see citing works
“(Figure 3E,F), a disease-specific form present across TDP-43 proteinopathies (27).”
BackgroundDantuma, N. P., Lindsten, K., Glas, R., Jellne, M., & Masucci, M. G. (2000) · Nature Biotechnology · doi:10.1038/75406 · Cited by 600 · cited 1× · see citing works
“Although overall proteasome activity was not affected by Nlk overexpression (Supplemental Figure 3J), as determined using a Ub G76V -GFP reporter (20), treatment with the al clones were classified by amount of intact Nlk protein, and to ensure that the phenotypes observed were a result of Nlk…”
Wils, H., Kleinberger, G., Janssens, J., Pereson, S., Joris, G., Cuijt, I., Smits, V., Groote, C. C., Broeckhoven, C. V., & Kumar‐Singh, S. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0912417107 · Cited by 592 · cited 2× · see citing works
“euthanasia at a humane endpoint) when bred to give rise to homozygous progeny (38).”
BackgroundMethodTherapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice
Becker, L. A., Huang, B., Bieri, G., Ma, R., Knowles, D. A., Jafar-Nejad, P., Messing, J., Kim, H. J., Soriano, A., Auburger, G., et al. (2017) · Nature · doi:10.1038/nature22038 · Cited by 571 · cited 5× · see citing works
“For this reason, alternative approaches that mitigate pathologies commonly observed 295 across sALS and fALS, such as pathological TDP-43 aggregation (34) or premature poly296”
BackgroundMethodInfluentialSelf-citationAntisense oligonucleotide therapy for neurodegenerative disease
Smith, R. A. (2006) · Journal of Clinical Investigation · doi:10.1172/jci25424 · Cited by 506 · cited 1× · see citing works
“In recent years, ASO-based approaches have shown promise in pre181 clinical models of various motor neuron diseases (33-35), as well as in human clinical trials for 182”
BackgroundSwayze, E. E., Siwkowski, A. M., Wancewicz, E. V., Migawa, M. T., Wyrzykiewicz, T. K., Hung, G., Monia, B. P., & Bennett, A. C. F. (2006) · Nucleic Acids Research · doi:10.1093/nar/gkl1071 · Cited by 473 · see citing works
Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases
Nakashima-Yasuda, H., Uryu, K., Robinson, J., Xie, S. X., Hurtig, H., Duda, J. E., Arnold, S. E., Siderowf, A., Grossman, M., Leverenz, J. B., et al. (2007) · Acta Neuropathologica · doi:10.1007/s00401-007-0261-2 · Cited by 468 · cited 1× · see citing works
“…DNA-binding protein 43 kDa (TDP-43) are observed in approximately 97% of all patients, including patients with sporadic ALS (sALS) or familial ALS (fALS) (1–3), as well as in subsets of patients with frontotemporal dementia (FTD) (1, 3), Alzheimer’s disease (4), and Parkinson’s disease (5).”
BackgroundGeneration and expansion of highly pure motor neuron progenitors from human pluripotent stem cells
Du, Z., Chen, H., Liu, H., Lü, J., Qian, K. X., Huang, C., Zhong, X., Fan, F., & Zhang, S. (2015) · Nature Communications · doi:10.1038/ncomms7626 · Cited by 459 · see citing works
Regulation of TFEB and V‐ATPases by mTORC1
Peña‐Llopis, S., Vega-Rubín-de-Celis, S., Schwartz, J. C., Wolff, N. C., Tran, T. A. T., Zou, L., Xie, X., Corey, D. R., & Brugarolas, J. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.257 · Cited by 456 · cited 1× · see citing works
“subcellular localization and activity of Tfeb (16, 18-21).”
BackgroundAutophagy induction enhances TDP43 turnover and survival in neuronal ALS models
Barmada, S. J., Serio, A., Arjun, A., Bilican, B., Daub, A., Ando, D. M., Tsvetkov, A., Pleiss, M., Li, X., Peisach, D., et al. (2014) · Nature Chemical Biology · doi:10.1038/nchembio.1563 · Cited by 431 · see citing works
A Simple Composite Phenotype Scoring System for Evaluating Mouse Models of Cerebellar Ataxia
Guyenet, S. J., Furrer, S. A., Damian, V. M., Baughan, T. D., La Spada, A. R., & Garden, G. A. (2010) · Journal of Visualized Experiments · doi:10.3791/1787 · Cited by 403 · cited 2× · see citing works
“573 Motor behavior of Thy1-TDPTg animals and littermate controls was examined at P14, P16, P18, 574 P20, and P22 as previously described (34, 39), with minor modifications.”
Wang, I.-F., Guo, B.-S., Liu, Y.-C., Wu, C.-C., Yang, C.-H., Tsai, K.-J., & Shen, C.-K. J. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1206362109 · Cited by 377 · cited 1× · see citing works
“Because soluble and aggregated forms of TDP-43 and its cleavage products can be cleared through the ALP (27–30), we aimed to determine whether TDP-43 levels could be modulated through altering Nlk levels.”
Kaimal, V., Bardes, E. E., Tabar, S., Jegga, A. G., & Aronow, B. J. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq418 · Cited by 375 · cited 3× · see citing works
“Biological pathways and cellular components with enrichment scores greater than 1.3 (-log Bonferroni-corrected p-value for ToppCluster, and -log Benjamini-Hochberg corrected p-value for IPA) were considered significant.”
MethodInfluentialProtein kinase C controls lysosome biogenesis independently of mTORC1
Li, Y., Xu, M., Ding, X., Chen, Y., Song, Z., Chen, L., Huang, X., Wang, X., Jian, Y., Tang, G., et al. (2016) · Nature Cell Biology · doi:10.1038/ncb3407 · Cited by 348 · cited 1× · see citing works
“subcellular localization and activity of Tfeb (16, 18-21).”
BackgroundThomas, C. A., Tejwani, L., Trujillo, C. A., Negraes, P. D., Herai, R. H., Mesci, P., Macia, A., Crow, Y. J., & Muotri, A. R. (2017) · Cell Stem Cell · doi:10.1016/j.stem.2017.07.009 · Cited by 330 · see citing works
Self-citationAntisense oligonucleotide therapy for spinocerebellar ataxia type 2
Scoles, D. R., Meera, P., Schneider, M. D., Paul, S., Dansithong, W., Figueroa, K. P., Hung, G., Rigo, F., Bennett, C. F., Otis, T. S., et al. (2017) · Nature · doi:10.1038/nature22044 · Cited by 319 · cited 1× · see citing works
“been the disease-causing protein itself (33, 42-45).”
Self-citationAntisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models
McCampbell, A., Cole, T., Wegener, A. J., Tomassy, G. S., Setnicka, A., Farley, B. J., Schoch, K. M., Hoye, M. L., Shabsovich, M., Sun, L., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci99081 · Cited by 279 · cited 1× · see citing works
“been the disease-causing protein itself (33, 42-45).”
Scotter, E. L., Vance, C. A., Nishimura, A. L., Lee, Y., Chen, H.-J., Urwin, H., Sardone, V., Mitchell, J. C., Rogelj, B., Rubinsztein, D. C., et al. (2014) · Journal of Cell Science · doi:10.1242/jcs.140087 · Cited by 265 · cited 7× · see citing works
“Nlk regulates TDP-43 levels The ALP is one of two primary systems for intracellular protein degradation and has been implicated to be defective in some forms of ALS (22, 23).”
BackgroundInfluentialMultistep regulation of TFEB by MTORC1
Vega-Rubín-de-Celis, S., Peña-Llopis, S., Konda, M., & Brugarolas, J. (2017) · Autophagy · doi:10.1080/15548627.2016.1271514 · Cited by 215 · see citing works
Filiano, A. J., Martens, L. H., Young, A. H., Warmus, B. A., Zhou, P., Diaz‐Ramirez, G., Jiao, J., Zhang, Z., Huang, E. J., Gao, F., et al. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.6103-11.2013 · Cited by 172 · cited 1× · see citing works
“but not to stress granules that are membraneless structures implicated in ALS pathogenesis (10) 71”
BackgroundLieberman, A. P., Yu, Z., Murray, S., Peralta, R., Low, A., Guo, S., Yu, X. X., Cortes, C. J., Bennett, C. F., Monia, B. P., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.02.008 · Cited by 169 · cited 2× · see citing works
“been the disease-causing protein itself (33, 42-45).”
BackgroundPolyglutamine-expanded androgen receptor interferes with TFEB to elicit autophagy defects in SBMA
Cortés, C. J., Miranda, H. C., Frankowski, H., Batlevi, Y., Young, J. E., Le, A. T., Ivanov, N., Sopher, B. L., Carromeu, C., Muotri, A. R., et al. (2014) · Nature Neuroscience · doi:10.1038/nn.3787 · Cited by 164 · see citing works
Shortened TDP43 isoforms upregulated by neuronal hyperactivity drive TDP43 pathology in ALS
Weskamp, K., Tank, E. M. H., Miguez, R., McBride, J. P., Gómez, N., White, M. A., Lin, Z., Moreno-Gonzalez, C., Serio, A., Sreedharan, J., et al. (2019) · Journal of Clinical Investigation · doi:10.1172/jci130988 · Cited by 127 · see citing works
Friedrich, J., Kordasiewicz, H. B., O’Callaghan, B., Handler, H. P., Wagener, C., Duvick, L., Swayze, E. E., Rainwater, O., Hofstra, B., Benneyworth, M., et al. (2018) · JCI Insight · doi:10.1172/jci.insight.123193 · Cited by 121 · cited 1× · see citing works
“been the disease-causing protein itself (33, 42-45).”
A Simple Composite Phenotype Scoring System for Evaluating Mouse Models of Cerebellar Ataxia
Guyenet, S. J., Furrer, S. A., Damian, V. M., et al. (2010) · Journal of Visualized Experiments · doi:10.3791/1787-v · Cited by 121 · see citing works
Synergistic effect between proteasome and autophagosome in the clearance of polyubiquitinated TDP‐43
Urushitani, M., Sato, T., Bamba, H., Hisa, Y., & Tooyama, I. (2010) · Journal of Neuroscience Research · doi:10.1002/jnr.22243 · Cited by 114 · cited 7× · see citing works
“Nlk regulates TDP-43 levels The ALP is one of two primary systems for intracellular protein degradation and has been implicated to be defective in some forms of ALS (22, 23).”
BackgroundInfluentialHatzipetros, T., Bogdanik, L. P., Tassinari, V. R., Kidd, J. D., Moreno, A. J., Davis, C., Osborne, M. A., Austin, A., Vieira, F. G., Lutz, C. M., et al. (2013) · Brain Research · doi:10.1016/j.brainres.2013.10.013 · Cited by 108 · cited 1× · see citing works
“159 Although male and female Prp-TDPA315T/+ hemizygous mice display differences in survival that 160 are likely due to sex differences in gastrointestinal complications that are associated with lethality 161 (29), genetic reduction of Nlk by 50% increased median survival of male and female Prp162 TDPA315T/+ mice by ab…”
BackgroundHydraulic Extrusion of the Spinal Cord and Isolation of Dorsal Root Ganglia in Rodents
Richner, M., Jager, S. E., Siupka, P., & Vægter, C. B. (2017) · Journal of Visualized Experiments · doi:10.3791/55226 · Cited by 107 · cited 1× · see citing works
“482 Spinal cords were then extracted by hydraulic extrusion, as described previously (59).”
MethodLiu, J., Shinobu, L. A., Ward, C. M., Young, D., & Cleveland, D. W. (2005) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2005.03054.x · Cited by 99 · cited 1× · see citing works
“which was defined as the first time point in which weight gain was no longer observed (30, 31), 165 was significantly delayed in male mice with a 50% genetic reduction of Nlk (Supplemental Figure 166 6C).”
BackgroundLing, S., Dastidar, S. G., Tokunaga, S., Ho, W. Y., Lim, K., Ilieva, H. S., Parone, P. A., Tyan, S.-H., Tse, T. M., Chang, J., et al. (2019) · eLife · doi:10.7554/elife.40811 · Cited by 85 · see citing works
Role of autophagy in the pathogenesis of amyotrophic lateral sclerosis
Lee, J. K., Shin, J. H., Lee, J. E., & Choi, E.-J. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2015.08.005 · Cited by 84 · cited 16× · see citing works
“The therapeutic benefits of Nlk reduction on motor behavior, neurodegeneration and its associated astrogliosis, and survival of two independent TDP-43 animal models provide strong proof-of-principle evidence for this promising approach in TDP-43 proteinopathies, both in instances in which TARDBP mutations are present…”
BackgroundInfluentialTDP-43 controls lysosomal pathways thereby determining its own clearance and cytotoxicity
Leibiger, C., Deisel, J., Aufschnaiter, A., Ambros, S., Tereshchenko, M., Verheijen, B. M., Büttner, S., & Braun, R. J. (2018) · Human Molecular Genetics · doi:10.1093/hmg/ddy066 · Cited by 68 · cited 1× · see citing works
“…have not been reported to display overt impairments in autophagy/lysosome function, likely due to the aggressive disease progression in these models that contributes to premature lethality prior to robust lysosomal dysfunction that may eventually be induced by aberrant TDP-43 aggregation (50).”
Coughlan, K. S., Halang, L., Woods, I., et al. (2016) · Disease Models & Mechanisms · doi:10.1242/dmm.024786 · Cited by 61 · cited 1× · see citing works
“Finally, because altering diet may affect 206 the course of disease in transgenic ALS mouse models (40), we raised an independent cohort of 207 Thy1-TDPTg/Tg animals on a high fat/gel food diet and observed a similar improvement in motor 208 behavior with a greater extension of survival with P1 Nlk ASO injections (Sup…”
MethodLi, S.-Z., Zhang, H.-H., Liang, J.-B., Song, Y., Jin, B.-X., Xing, N.-N., Fan, G.-C., Du, R.-L., & Zhang, X.-D. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2014.03.028 · Cited by 35 · cited 1× · see citing works
“…are involved in central nervous system disorders (9) as well as indirectly to affect inflammation through altered NF-κ B transcriptional activity (10), the physiological role of Nlk and the general effects of its modulation in the adult nervous system have not yet been comprehensively examined.”
Sakaguchi, T., Irie, T., Kawabata, R., Yoshida, A., Maruyama, H., & Kawakami, H. (2011) · Neuroscience Letters · doi:10.1016/j.neulet.2011.10.040 · Cited by 32 · cited 7× · see citing works
“Because no known neurological condition in humans has been associated with a reduction of Nlk, mice with partial genet-ic reduction of Nlk display no pathological (neurodegenerative or inflammatory), survival, or cognitive changes up to 52 weeks (57), and mice with postnatal whole-body conditional ablation of Nlk are…”
InfluentialPolyglutamine Disease Toxicity Is Regulated by Nemo-like Kinase in Spinocerebellar Ataxia Type 1
Ju, H., Kokubu, H., Todd, T. W., Kahle, J. J., Kim, S., Richman, R., Chirala, K., Orr, H. T., Zoghbi, H. Y., & Lim, J. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.3465-12.2013 · Cited by 31 · cited 6× · 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-citationHydraulic Extrusion of the Spinal Cord and Isolation of Dorsal Root Ganglia in Rodents
Richner, M., Jager, S. E., Siupka, P., et al. (2017) · Journal of Visualized Experiments · doi:10.3791/55226-v · Cited by 29 · 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 · cited 4× · 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-citationNemo-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 · cited 1× · see citing works
“Although it is known that Nlk directly interacts with several other proteins that are involved in central nervous system disorders (9) as well as indirectly to affect inflammation through altered NF-κ B transcriptional activity (10), the physiological role of Nlk and the general effects of its…”
Self-citationMicroglia 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 · cited 2× · see citing works
“…survival, or cognitive changes up to 52 weeks (57), and mice with postnatal whole-body conditional ablation of Nlk are grossly normal (57), we believe targeted reduction of Nlk or its downstream effectors to increase ALP function is a potentially generalizable therapeutic strategy…”
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Advances and Challenges in Gene Therapy for Neurodegenerative Diseases: A Systematic Review
García-González, N., Gonçalves-Sánchez, J., Gómez‐Nieto, R., Gonçalves, J. M., & López, D. E. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252312485 · Cited by 32 · see citing works
“Notably, some NDDs share pathogenic mechanisms, which suggest common therapeutic targets.”
MAPK Signaling in the Interplay Between Oxidative Stress and Autophagy
Desideri, E., Castelli, S., & Ciriolo, M. R. (2025) · Antioxidants · doi:10.3390/antiox14060662 · Cited by 23 · see citing works
“They show that in neuronal cells NLK inhibits lysosomal biogenesis and autophagy by promoting the destabilization of nuclear TFEB [126].”
Wu, J., Xu, W., Su, Y., Wang, G., & Ma, J. (2024) · Acta Pharmacologica Sinica · doi:10.1038/s41401-024-01416-3 · Cited by 17 · see citing works
“Although mutations in TARDBP, the gene encoding transactive response DNA-binding protein 43 kDa (TDP-43), account for fewer than 1% of ALS cases, TDP-43-positive aggregates are present in nearly all ALS patients [122].”
Beckers, J., & Damme, P. V. (2025) · Autophagy Reports · doi:10.1080/27694127.2025.2474796 · Cited by 16 · see citing works
Hidalgo-Álvarez, J., Salas-Lucia, F., Cruz, D. V., Fonseca, T. L., & Bianco, A. C. (2023) · JCI Insight · doi:10.1172/jci.insight.173780 · Cited by 15 · see citing works
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
“We have recently identified Nlk as a negative regulator of the lysosome in neurons (46).”
BackgroundSelf-citationXiao, C., Gu, X., Feng, Y., & Shen, J. (2024) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2024.1367106 · Cited by 11 · see citing works
Significance of gene therapy in neurodegenerative diseases
Wang, L., Ma, L., Gao, Z., Wang, Y., & Qiu, J. (2025) · Frontiers in Neuroscience · doi:10.3389/fnins.2025.1515255 · Cited by 7 · see citing works
“ASOs targeting STMN2 can also be designed to restore the expression of exon-2a in STMN2 mRNA, leading to normal STMN2 expression (Baughn et al., 2023).”
InfluentialYang, Q., Ma, H., Yang, L., Jiang, M., Liu, X., & Bai, Z.-T. (2025) · Science Signaling · doi:10.1126/scisignal.adt1936 · Cited by 6 · see citing works
Nemo-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
“NLK depletion mitigates disease phenotypes not only in Drosophila and murine models of ALS but also in murine models of spinobulbar muscular atrophy and spinocerebellar ataxia (16–18).”
Progranulin deficiency does not exacerbate TDP-43 pathology in TDP-43 transgenic mouse models
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Chemical and Molecular Strategies in Restoring Autophagic Flux in TDP-43 Proteinopathy
Jamerlan, A., & Hulme, J. (2026) · Molecules · doi:10.3390/molecules31060924 · Cited by 1 · see citing works
“I κ B kinase (IKK), glycogen synthase kinase-3 beta (GSK3 β ), and Nemo-like kinase (NLK) are stress-and inflammation-response kinases that reconfigure PTMs, phase behav-https ior, and trafficking, thereby influencing aberrant TDP-43 targeting by the UPS cascade or ALP [47,173–175].”
Targeting TDP-43 in sporadic amyotrophic lateral sclerosis
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An Overview of Protein Kinase Inhibitors
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Mechanisms of autophagy–lysosome pathway impairment in Alzheimer's disease
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- Authors
- Tejwani, L., Jung, Y., Kokubu, H., Sowmithra, S., Ni, L., Lee, C., Sanders, B., Lee, P. J., Xiang, Y., Luttik, K., Soriano, A., Yoon, J., Park, J., Ro, H. H., Ju, H., Liao, C., Tieze, S. M., Rigo, F., Jafar-Nejad, P., & Lim, J.
- Affiliations
- Yale University (US)
- Ionis Pharmaceuticals (United States) (US)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2023-08-15
- Volume
- 133
- Issue
- 16
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC10425213
- OpenAlex
- W4382632516
- Semantic Scholar
- 3681f3ffe722138cec320d12d13c4eaaca865683
- Cited by
- 17
- References
- 75
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 4 · 2023: 1 · 2021: 1
- FWCI
- 2.33
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Clinical Investigation (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute of Neurological Disorders and Stroke (NS083706,NS088321,NS007224)
- National Institute of Mental Health (MH119803)
- Lo Graduate Fellowship for Excellence in Stem Cell Research (N/A)
- Gruber Science Fellowship (N/A)
- Yale College First-Year Fellowship in the Sciences & Engineering (N/A)
- National Institute on Aging (AG066447,AG076154,AG074609)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- Nemo-like kinase, lysosomal biogenesis, TDP-43, TDP-43 proteinopathy, amyotrophic lateral sclerosis, protein aggregation, autophagy-lysosome pathway, protein quality control, neurodegeneration, frontotemporal dementia, Alzheimer's disease, Parkinson's disease, therapeutic target
- MeSH terms
- Amyotrophic Lateral Sclerosis, Animals, DNA-Binding Proteins, Humans, Lysosomes, Protein Serine-Threonine Kinases, Neurodegenerative Diseases, Mice
About these checks
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.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-18.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-18.
Cited sources are checked by gpt-6-sol.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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