SCA1-like Disease in Mice Expressing Wild-Type Ataxin-1 with a Serine to Aspartic Acid Replacement at Residue 776
Open accessAbstract
Glutamine tract expansion triggers nine neurodegenerative diseases by conferring toxic properties to the mutant protein. In SCA1, phosphorylation of ATXN1 at Ser776 is thought to be key for pathogenesis. Here, we show that replacing Ser776 with a phosphomimicking Asp converted ATXN1 with a wild-type glutamine tract into a pathogenic protein. ATXN1[30Q]-D776-induced disease in Purkinje cells shared most features with disease caused by ATXN1[82Q] having an expanded polyglutamine tract. However, in contrast to disease induced by ATXN1[82Q] that progresses to cell death, ATXN1[30Q]-D776 failed to induce cell death. These results support a model where pathogenesis involves changes in regions of the protein in addition to the polyglutamine tract. Moreover, disease initiation and progression to neuronal dysfunction are distinct from induction of cell death. Ser776 is critical for the pathway to neuronal dysfunction, while an expanded polyglutamine tract is essential for neuronal death.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
S776 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).”
From Polyglutamine Disease Toxicity Is Regulated by Nemo-like Kinase in Spinocerebellar Ataxia Type 1 (2013) · cites this paper as Duvick et al., 2010
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 measuredPhosphorylation 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).”
From Polyglutamine Disease Toxicity Is Regulated by Nemo-like Kinase in Spinocerebellar Ataxia Type 1 (2013) · cites this paper as Duvick et al., 2010
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
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 31 · Cited by 145
Research works printed but not linked: 27
- Bates G Huntingtin aggregation and toxicity in Huntingon's disease. Lancet 2003 361 1642 1644 12747895
- Beers DR Henkel JS Zhao W Wang J Yen AA Siklos L McKercher SR Appel SH Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral scelorsis. Proc. Natl. Acad. Sci. USA 2006 103 16021 16026 17043238 PMC1613228
- Burright EN Clark HB Servadio A Matilla T Feddersen RM Yunis WS Duvick LA Zoghbi HY Orr HT SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat. Cell 1995 82 937 948 7553854
- Clark HB Burright EN Yunis WS Larson S Wilcox C Hartman B Matilla A Zoghbi HY Orr HT Purkinje cell expression of a mutant allele of SCA1 in transgenic mice leads to disparate effects on motor behaviors followed by a progressive cerebellar dysfunction and histological alterations. J. Neurosci 1997 17 7385 7395 9295384 PMC6573461
- DiFiglia M Sapp E Chase KO Davies SW Bates GP Vonsattel JP Aronin N Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neuritis in brain. Science 1997 277 1990 1993 1997 9302293
- Emamian ES Kaytor MD Duvick LA Zu T Tousey SK Zoghbi HY Clark HB Orr HT Serine 776 of ataxin-1 is critical for polyglutamine-induced disease in SCA1 transgenic mice. Neuron 2003 38 375 387 12741986
- Freemeau RT Troyer MD Pahner I Nygaard GO Tran CH Reimer RJ Bellocchio EE Fortin D Storm-Mathisen J Edwards RH The expression of vesicular glutamate transporters defines two classes of excitatory synapse. Neuron 2001 31 247 260 11502256
- Fuijwara H Hasegawa M Dohmae N Kawashima A Masliah E Goldberg MS Shen J Takio K Iwatsubo T Alpha-synuclein is phosphorylated in synucleinopathy lesions. Nat. Cell Biol 2002 4 160 164 11813001
- Graham RK Deng Y Slow EJ Haigh B Bissada N Lu G Pearson J Shehadeh J Bertram L Murphy Z Warby SC Doty CN Roy S Wellington CL Leavitt BR Raymond LA Nicholson DW Hayden MR Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin. Cell 2006 125 1179 1191 16777606
- Gray M Shirasaki DI Cepaeda C André VM Wilburn B Lu XH Tao J Yamazaki I Li SH Sun YE Li XJ Levine MS Yang XW Full-length human mutant huntingtin with a stable polyglutamine repeat can elicit progressive and selective neuropathologies in BACHD mice. J. Neurosci 2008 28 6182 6195 18550760 PMC2630800
- Gu X Greiner ER Mishra R Kodali R Osmand A Finkbeiner S Steffan JS Thompson LM Wetzel R Yang XW Serines 13 and 16 are critical determinants of full-length mutant huntingtin induced disease pathogenesis in HD mice. Neuron 2009 64 828 840 20064390 PMC2807408
- Gutekunst CA Li SH Yi H Mulroy JS Kuemmerle S Jones R Rye D Ferrante RJ Hersch SM Li XJ Nuclear and neuropil aggregates in Huntington's disease: relationship to neuropathology. J. Neurosci 1999 19 2522 2534 10087066 PMC6786077
- Ito M The Cerebellum and Neural Control 1984 Raven Press, New York New York
- Katsuno M Adachi H Kume A Li M Nakagomi Y Niwa H Sang C Kobayashi Y Doyu M Sobue G Testosterone reduction prevents phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy. Neuron 2002 35 843 854 12372280
- Kim YJ Yi Y Sapp E Wang Y Cuiffo B Kegel KB Qin ZH Aronin N DiFiglia M Caspase 3-cleaved N-terminal fragments of wild-type and mutant huntingtin are present in normal and Huntington's disease brains, associate with membranes, and undergo calpain-dependent proteolysis. Proc. Natl. Acad. Sci. USA 2001 98 12784 12789 11675509 PMC60131
- Klement IA Skinner PJ Kaytor MD Yi H Hersch SM Clark HB Zoghbi HY Orr HT Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice. Cell 1998 95 41 53 9778246
- Li L-B Yu Z Teng X Bonini NM RNA toxicity is a component of ataxin-3 degeneration in Drosophila. Nature 2008 453 1107 1111 18449188 PMC2574630
- Lim J Crespo-Barreto J Jafar-Nejad P Bowman AB Richman R Hill DE Orr HT Zoghbi HY Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1. Nature 2008 452 713 719 18337722 PMC2377396
- Manto M-U The wide spectrum of spinocerebellar ataxias (SCAs). Cerebellum 2005 4 2 6 15895552
- Nakagawa S Watanabe M Isobe T Kondo H Inoue Y Cytological compartmentalization in the staggerer cerebellum, as revealed by calbindin immunohistochemistry for Purkinje cells. J. Comp. Neurol 1998 395 112 120 9590549
- Orr HT Zoghbi HY Trinucleotide repeat disorders. Ann. Rev. Neurosci 2007 30 575 621 17417937
- Pallier PN Drew CJ Morton AJ The detection and measurement of locomotor deficits in a transgenic mouse model of Huntington's disease are task- and protocol-dependent: influence of non-motor factors on locomotor function. Brain Res Bull 2009 78 347 355 19010400
- Ross CA Poirier MA Wanker EE Amzel M Polyglutamine fibrillogenesis: the pathway unfolds. Proc. Natl. Acad. Sci. USA 2003 100 1 3 12509507 PMC140861
- Serra HG Duvick L Zu T Carlson' K Stevens S Jorgensen N Lysholm A Burright E Zoghbi HY Clark HB Andresen JM Orr HT RORα-mediated Purkinje cell development determines disease severity in adult SCA1 mice. Cell 2006 127 697 708 17110330
- Servadio A Koshy B Armstrong D Antalffy B Orr HT Zoghbi HY Expression analysis of the ataxin-1 protein in tissues from normal and spinocerebellar ataxia type 1 individuals. Nat. Genet 1995 10 94 98 7647801
- Tsuda H Jafar-Nejad H Patel AJ Sun Y Chen HK Rose MF Venken KJ Botas J Orr HT Bellen HJ Zoghbi HY The AXH domain of Ataxin-1 mediates neurodegeneration through its interaction with Gfi-1/Senseless proteins. Cell 2005 122 633 644 16122429
- Zu T Duvick LA Kaytor MD Berlinger M Zoghbi HY Clark HB Orr HT Recovery from polyglutamine-Induced neurodegeneration in conditional SCA1 transgenic mice. J. Neurosci 2004 24 8853 8861 15470152 PMC6729947
- Authors
- Duvick, L., Barnes, J., Ebner, B., Agrawal, S., Andresen, M., Lim, J., Giesler, G. J., Zoghbi, H. Y., & Orr, H. T.
- Affiliations
- University of Minnesota (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Orr, Harry T.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2010-09
- Volume
- 67
- Issue
- 6
- Pages
- 929-935
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC2946945
- OpenAlex
- W2035357631
- Cited by
- 145
- References
- 31
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 5 · 2023: 9 · 2022: 5 · 2021: 11 · 2020: 9 · 2019: 4 · 2018: 12 · 2017: 9 · 2016: 5 · 2015: 11 · 2014: 13 · 2013: 8 · 2012: 14
- FWCI
- 6.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1050 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R37NS022920, NS 045667, NS062561, F31NS062561, NS022920, R01NS022920, R01NS045667, R01NS048944, NS048944, R01NS027699)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- spinocerebellar ataxia type 1, ataxin-1, polyglutamine expansion, neurodegeneration, Purkinje cells, neuronal cell death, neuronal dysfunction, mouse model
- MeSH terms
- Ataxins, Ataxin-1, Animals, Aspartic Acid, Cerebellum, Dendrites, Disease Models, Animal, Gene Expression Regulation, Mice, Transgenic, Motor Activity, Mutation, Nerve Tissue Proteins, Neural Pathways, Nuclear Proteins, Purkinje Cells, Serine, Spinocerebellar Ataxias, Rotarod Performance Test, Vesicular Glutamate Transport Protein 2, Mice, Calbindins, S100 Calcium Binding Protein G
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.
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 ›
Are you an author, or do you see a problem with this page? Request a review
