ArticleHuman molecular genetics2014
Overexpression of the calpain-specific inhibitor calpastatin reduces human alpha-Synuclein processing, aggregation and synaptic impairment in [A30P]αSyn transgenic mice.
Article in Human molecular genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 77 papers.
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Who cites it
77 citing papers in PubMed, 108 citations in OpenAlex.
- From synaptic development to degeneration: a narrative review of small molecule strategies targeting alpha-synuclein in Parkinson's disease.Metabolic brain disease · 2026Review
- DYRK1A and Parkinson's disease, facts and hypotheses.Neurobiology of disease · 2026Review
- A small-molecule stabilizer of the calpastatin-calpain-2 complex restores mitochondrial function and mitigates neurodegeneration.Science advances · 2026Article
- Review
- 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 Dopaminergic Neuron Degeneration in Parkinson's Disease: A Comprehensive Review.Current neuropharmacology · 2026Review
- Using fibre photometry with a fluorescence resonance energy transfer-based biosensor to test efficacy of calpain inhibitorsBrain communications · 2026Article
- Parkinson's disease mutant Miro1 causes mitochondrial dysfunction and dopaminergic neuron loss.Brain : a journal of neurology · 2025Article
- Differential role of C-terminal truncations on alpha-synuclein pathology and Lewy body formation.NPJ Parkinson's disease · 2025Article
- Tauopathies: Calmodulin Regulates Tau Hyperphosphorylation and Its Transformation into Disease-Specific Aggregates.Biomolecules · 2025Review
- Vimentin network dysregulation mediates neurite deficits inScience advances · 2025Article
- The Search for a Universal Treatment for Defined and Mixed Pathology Neurodegenerative Diseases.International journal of molecular sciences · 2024Review
- Mechanisms of autophagy-lysosome dysfunction in neurodegenerative diseases.Nature reviews. Molecular cell biology · 2024Review
- The Complex Interplay between Toxic Hallmark Proteins, Calmodulin-Binding Proteins, Ion Channels, and Receptors Involved in Calcium Dyshomeostasis in Neurodegeneration.Biomolecules · 2024Review
- Expression of calpastatin hcast 3-25 and activity of the calpain/calpastatin system in human glioblastoma stem cells: possible involvement of hcast 3-25 in cell differentiation.Frontiers in molecular biosciences · 2024Article
- Synucleinopathies: Intrinsic and Extrinsic Factors.Cell biochemistry and biophysics · 2023Article
- The Bidirectional Interplay of α-Synuclein with Lipids in the Central Nervous System and Its Implications for the Pathogenesis of Parkinson's Disease.International journal of molecular sciences · 2023Review
- Inhibition of Protein Aggregation and Endoplasmic Reticulum Stress as a Targeted Therapy for α-Synucleinopathy.Pharmaceutics · 2023Review
- The Parkinson-Associated Toxin Paraquat Shifts Physiological α-Synuclein Tetramers toward Monomers That Can Be Calpain-Truncated and Form Oligomers.The American journal of pathology · 2023Article
- Molecular Mechanisms and Pathophysiological Significance of Eryptosis.International journal of molecular sciences · 2023Review
17 more citing papers are in PubMed but not listed here.
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Authors and funding
16 authors at 7 institutions in 4 countries.
Funding
Abstract
Lewy bodies, a pathological hallmark of Parkinson's disease (PD), contain aggregated alpha-synuclein (αSyn), which is found in several modified forms and can be discovered phosphorylated, ubiquitinated and truncated. Aggregation-prone truncated species of αSyn caused by aberrant cleavage of this fibrillogenic protein are hypothesized to participate in its sequestration into inclusions subsequently leading to synaptic dysfunction and neuronal death. Here, we investigated the role of calpain cleavage of αSyn in vivo by generating two opposing mouse models. We crossed into human [A30P]αSyn transgenic (i) mice deficient for calpastatin, a calpain-specific inhibitor, thus enhancing calpain activity (SynCAST(-)) and (ii) mice overexpressing human calpastatin leading to reduced calpain activity (SynCAST(+)). As anticipated, a reduced calpain activity led to a decreased number of αSyn-positive aggregates, whereas loss of calpastatin led to increased truncation of αSyn in SynCAST(-). Furthermore, overexpression of calpastatin decreased astrogliosis and the calpain-dependent degradation of synaptic proteins, potentially ameliorating the observed neuropathology in [A30P]αSyn and SynCAST(+) mice. Overall, our data further support a crucial role of calpains, particularly of calpain 1, in the pathogenesis of PD and in disease-associated aggregation of αSyn, indicating a therapeutic potential of calpain inhibition in PD.
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