ArticleCellular and molecular life sciences : CMLS2022
Calpains as novel players in the molecular pathogenesis of spinocerebellar ataxia type 17.
Article in Cellular and molecular life sciences : CMLS, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 11 citations in OpenAlex.
- The DNA/RNA autophagy protein SIDT2 as a novel neuropathological hallmark in Huntington disease.Brain pathology (Zurich, Switzerland) · 2026Article
- Loss-of-function variants in the CAPN1 activator CD99L2 cause X-linked spastic ataxia.Nature communications · 2026Article
- Investigating the pathogenic role of calpain proteases and the therapeutic potential of their inhibition in mice modelling Machado-Joseph disease.Human molecular genetics · 2026Article
- Molecular Mechanisms of Spinocerebellar Ataxia Type 17.Molecular neurobiology · 2025Review
- The parkin V380L variant is a genetic modifier of Machado-Joseph disease with impact on mitophagy.Acta neuropathologica · 2024Article
- Article
- Calpain signaling: from biology to therapeutic opportunities in neurodegenerative disorders.Frontiers in veterinary science · 2023Review
- Calpain-mediated proteolysis as driver and modulator of polyglutamine toxicity.Frontiers in molecular neuroscience · 2022Review
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
Abstract
Spinocerebellar ataxia type 17 (SCA17) is a neurodegenerative disease caused by a polyglutamine-encoding trinucleotide repeat expansion in the gene of transcription factor TATA box-binding protein (TBP). While its underlying pathomechanism is elusive, polyglutamine-expanded TBP fragments of unknown origin mediate the mutant protein's toxicity. Calcium-dependent calpain proteases are protagonists in neurodegenerative disorders. Here, we demonstrate that calpains cleave TBP, and emerging C-terminal fragments mislocalize to the cytoplasm. SCA17 cell and rat models exhibited calpain overactivation, leading to excessive fragmentation and depletion of neuronal proteins in vivo. Transcriptome analysis of SCA17 cells revealed synaptogenesis and calcium signaling perturbations, indicating the potential cause of elevated calpain activity. Pharmacological or genetic calpain inhibition reduced TBP cleavage and aggregation, consequently improving cell viability. Our work underlines the general significance of calpains and their activating pathways in neurodegenerative disorders and presents these proteases as novel players in the molecular pathogenesis of SCA17.
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Registered trials
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.