ArticleProceedings of the National Academy of Sciences of the United States of America2012
Development of Purkinje cell degeneration in a knockin mouse model reveals lysosomal involvement in the pathogenesis of SCA6.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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34 citing papers in PubMed, 59 citations in OpenAlex.
- Experimental Models to Study Polyglutamine Spinocerebellar Ataxias: From Mechanisms to Therapeutic Developments.Cerebellum (London, England) · 2026Review
- Molecular hallmarks of neurodegeneration in polyglutamine spinocerebellar ataxias.Cell death & disease · 2025Review
- A dominant negative Kcnd3 F227del mutation in mice causes spinocerebellar ataxia type 22 (SCA22) by impairing ER and Golgi functioning.The Journal of pathology · 2025Article
- Ablation of TrkB from Enkephalinergic Precursor-Derived Cerebellar Granule Cells Generates Ataxia.Biology · 2024Article
- RREB1 regulates neuronal proteostasis and the microtubule network.Science advances · 2024Article
- Endosomal dysfunction contributes to cerebellar deficits in spinocerebellar ataxia type 6.eLife · 2023Article
- Chaperone-mediated autophagy in neurodegenerative diseases: mechanisms and therapy.Molecular and cellular biochemistry · 2023Review
- A neurodevelopmental disorder caused by a dysfunctionaleNeurologicalSci · 2023Article
- Cathepsin B in programmed cell death machinery: mechanisms of execution and regulatory pathways.Cell death & disease · 2023Review
- Article
- Consensus Paper: Strengths and Weaknesses of Animal Models of Spinocerebellar Ataxias and Their Clinical Implications.Cerebellum (London, England) · 2022Article
- W246G Mutant ELOVL4 Impairs Synaptic Plasticity in Parallel and Climbing Fibers and Causes Motor Defects in a Rat Model of SCA34.Molecular neurobiology · 2021Article
- What is the Pathogenic CAG Expansion Length in Huntington's Disease?Journal of Huntington's disease · 2021Review
- The proteasome regulator PI31 is required for protein homeostasis, synapse maintenance, and neuronal survival in mice.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Motor Performances of Spontaneous and Genetically Modified Mutants with Cerebellar Atrophy.Cerebellum (London, England) · 2019Review
- PLD3 epigenetic changes in the hippocampus of Alzheimer's disease.Clinical epigenetics · 2018Article
- Dendritic potassium channel dysfunction may contribute to dendrite degeneration in spinocerebellar ataxia type 1.PloS one · 2018Article
- Bicistronic CACNA1A Gene Expression in Neurons Derived from Spinocerebellar Ataxia Type 6 Patient-Induced Pluripotent Stem Cells.Stem cells and development · 2017Article
- Polyglutamine spinocerebellar ataxias - from genes to potential treatments.Nature reviews. Neuroscience · 2017Review
- Progression of Dysphagia in Spinocerebellar Ataxia Type 6.Dysphagia · 2017Article
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease caused by the expansion of a polyglutamine tract in the Ca(v)2.1 voltage-gated calcium channel. To elucidate how the expanded polyglutamine tract in this plasma membrane protein causes the disease, we created a unique knockin mouse model that modestly overexpressed the mutant transcripts under the control of an endogenous promoter (MPI-118Q). MPI-118Q mice faithfully recapitulated many features of SCA6, including selective Purkinje cell degeneration. Surprisingly, analysis of inclusion formation in the mutant Purkinje cells indicated the lysosomal localization of accumulated mutant Ca(v)2.1 channels in the absence of autophagic response. The lack of cathepsin B, a major lysosomal cysteine proteinase, exacerbated the loss of Purkinje cells and was accompanied by an acceleration of inclusion formation in this model. Thus, the pathogenic mechanism of SCA6 involves the endolysosomal degradation pathway, and unique pathological features of this model further illustrate the pivotal role of protein context in the pathogenesis of polyglutamine diseases.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.