ArticleNeuron2018
ATXN1-CIC Complex Is the Primary Driver of Cerebellar Pathology in Spinocerebellar Ataxia Type 1 through a Gain-of-Function Mechanism.
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Article in Neuron, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 73 papers.
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73citing papers in PubMed
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Who cites it
73 citing papers in PubMed, 116 citations in OpenAlex.
- Functional divergence of Capicua isoforms explains differential tissue vulnerability in neurological disease.Genes & development · 2026Article
- Modulating alternative splicing ofScience translational medicine · 2026Article
- Evaluating the Genetic Overlap Between Congenital Heart Disease and Neuroblastoma Risk.Pediatric blood & cancer · 2026Article
- Repeat-associated non-AUG translation as a common mechanism for the polyGln ataxias.Cell reports · 2026Article
- Translational Relevance of SCA1 Models for the Development of Therapies for Spinocerebellar Ataxia Type 1.Biomedicines · 2025Review
- Molecular hallmarks of neurodegeneration in polyglutamine spinocerebellar ataxias.Cell death & disease · 2025Review
- Functional divergence of Capicua isoforms explains differential tissue vulnerability in neurological disease.bioRxiv : the preprint server for biology · 2025Article
- Roots of Progress: Uncovering Cerebellar Ataxias Using iPSC Models.Biomedicines · 2025Review
- Identification of Splicing Regulatory Activity of ATXN1 and Its Associated Domains.Biomolecules · 2025Article
- Cas9 editing ofMolecular therapy. Nucleic acids · 2024Article
- CRISPR-Cas9-directed gene therapy for spinocerebellar ataxia type 1.Molecular therapy. Nucleic acids · 2024Article
- Increased intrinsic membrane excitability is associated with olivary hypertrophy in spinocerebellar ataxia type 1.Human molecular genetics · 2024Article
- Review
- Expanded ATXN1 alters transcription and calcium signaling in SCA1 human motor neurons differentiated from induced pluripotent stem cells.Neurobiology of disease · 2024Article
- Co-existence of Myelin Oligodendrocyte Glycoprotien Antibody-associated Disease (MOGAD) and Spinocerebellar Ataxia type 1 (SCA1): A case report.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2024Article
- Sequence composition changes in short tandem repeats: heterogeneity, detection, mechanisms and clinical implications.Nature reviews. Genetics · 2024Review
- Dynamic molecular network analysis of iPSC-Purkinje cells differentiation delineates roles of ISG15 in SCA1 at the earliest stage.Communications biology · 2024Article
- Review
- Longitudinal single-cell transcriptional dynamics throughout neurodegeneration in SCA1.Neuron · 2024Article
- Widespread alternative splicing dysregulation occurs presymptomatically in CAG expansion spinocerebellar ataxias.Brain : a journal of neurology · 2024Article
13 more citing papers are in PubMed but not listed here.
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Authors and funding
21 authors at 5 institutions in 1 country.
Maxime W C RousseauxJan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Tyler TschumperlinInstitute for Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
Hsiang-Chih LuJan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Elizabeth P LackeyJan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
Vitaliy V BondarJan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Ying-Wooi WanJan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Qiumin TanJan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Carolyn J AdamskiJan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Jillian FriedrichInstitute for Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
Kirk TwaroskiDepartment of Pediatrics, Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA.
Weili ChenDepartment of Pediatrics, Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA.
Jakub TolarDepartment of Pediatrics, Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA.
Christine HenzlerRISS Bioinformatics, Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN 55455, USA.
Ajay SharmaJan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Aleksandar BajićJan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Tao LinJan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
Lisa DuvickInstitute for Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
Zhandong LiuJan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA.
Roy V SillitoeJan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
Huda Y ZoghbiJan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Howard Hughes Medical Institute, Houston, TX 77030, USA. Electronic address: hzoghbi@bcm.edu.
Harry T OrrInstitute for Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: orrxx002@umn.edu.
University of Minnesota · USBaylor College of Medicine · USNeurological Research Institute · USTexas Children's Hospital · USHoward Hughes Medical Institute · US
Funding
Cell Signaling and NeurodegenerationR01NS045667 · NINDS · UNIVERSITY OF MINNESOTA TWIN CITIES · PI ORR, HARRY T. · 2003 to 2021
$8.8MMOLECULAR STUDIES OF SPINOCEREBELLAR ATAXIA TYPE 1R01NS027699 · NINDS · BAYLOR COLLEGE OF MEDICINE · PI HUDA Y ZOGHBI · 1989 to 2026
$8.8MSteps towards a paternal gene activation therapy for Angelman syndromeU54HD083092 · NICHD · BAYLOR COLLEGE OF MEDICINE · PI NELSON, DAVID LOREN, NEUL, JEFFREY L · 2014 to 2019
$7.8MMolecular Genetics of the SCA1 LocusR37NS022920 · NINDS · UNIVERSITY OF MINNESOTA TWIN CITIES · PI ORR, HARRY T. · 2004 to 2017
$5.9MMOLECULAR GENETICS OF THE SCA1 LOCUS ON CHROMOSOME 6PR01NS022920 · NINDS · UNIVERSITY OF MINNESOTA TWIN CITIES · PI ORR, HARRY T. · 1986 to 2022
$3.2MMOLECULAR STUDIES OF SPINOCEREBELLAR ATAXIS TYPE IR37NS027699 · NINDS · BAYLOR COLLEGE OF MEDICINE · PI ZOGHBI, HUDA Y · 2015 to 2021
$2.8MCEREBELLAR FUNCTION IN TREMORR01NS100874 · NINDS · BAYLOR COLLEGE OF MEDICINE · PI SILLITOE, ROY VINCENT · 2017 to 2021
$1.9MSYNAPTIC ORIGINS OF CEREBELLAR DISEASER01NS089664 · NINDS · BAYLOR COLLEGE OF MEDICINE · PI SILLITOE, ROY VINCENT · 2014 to 2018
$1.7MEvaluation of the in vivo effects of genes regulating Ataxin1 levels in SCA1 miceF32NS083091 · NINDS · BAYLOR COLLEGE OF MEDICINE · PI TAN, QIUMIN · 2013 to 2015
$141kNICHD NIH HHS U54 HD083092NINDS NIH HHS F32 NS083091NINDS NIH HHS R01 NS022920NINDS NIH HHS R01 NS027699NINDS NIH HHS R01 NS045667NINDS NIH HHS R01 NS089664NINDS NIH HHS R01 NS100874NINDS NIH HHS R37 NS022920NINDS NIH HHS R37 NS027699
Abstract
Polyglutamine (polyQ) diseases are caused by expansion of translated CAG repeats in distinct genes leading to altered protein function. In spinocerebellar ataxia type 1 (SCA1), a gain of function of polyQ-expanded ataxin-1 (ATXN1) contributes to cerebellar pathology. The extent to which cerebellar toxicity depends on its cognate partner capicua (CIC), versus other interactors, remains unclear. It is also not established whether loss of the ATXN1-CIC complex in the cerebellum contributes to disease pathogenesis. In this study, we exclusively disrupt the ATXN1-CIC interaction in vivo and show that it is at the crux of cerebellar toxicity in SCA1. Importantly, loss of CIC in the cerebellum does not cause ataxia or Purkinje cell degeneration. Expression profiling of these gain- and loss-of-function models, coupled with data from iPSC-derived neurons from SCA1 patients, supports a mechanism in which gain of function of the ATXN1-CIC complex is the major driver of toxicity.
Indexed as
AnimalsAtaxin-1Cells, CulturedCerebellumFemaleGain of Function MutationHumansMaleMiceMice, Inbred C57BLMice, TransgenicSpinocerebellar AtaxiasAtaxin-1ATXN1 protein, humanataxiaATXN1cerebellumCICneurodegenerationpolyglutamineRAN translationRNA toxicitytoxicity
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