ArticleNPJ Parkinson's disease2025
Differential role of C-terminal truncations on alpha-synuclein pathology and Lewy body formation.
Article in NPJ Parkinson's disease, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- Astrocytic cathepsin D promotes α-synuclein processing and Lewy neurite-like aggregate maturation.EMBO reports · 2026Article
- Differential proteostasis imbalance and the molecular basis of distinct synucleinopathies and tauopathies.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2026Review
- Cellular and systemic modifiers of alpha-synuclein proteostasis.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2026Review
- Development of an RNA aptamer as a therapeutic agent for synucleinopathies.Nature communications · 2026Article
- Blood-Based α-Synuclein Biomarkers in Parkinson's Disease: Molecular Diversity, Analytical Advances and Clinical Translation.International journal of molecular sciences · 2026Review
- Modeling Parkinson's pathology in human iPSC dopaminergic neurons uncovers key mechanisms of Lewy body formation and heterogeneity.Science advances · 2026Article
- DYRK1A and Parkinson's disease, facts and hypotheses.Neurobiology of disease · 2026Review
- Overexpression of phosphorylated and truncated α-Synuclein does not trigger Parkinsonian readouts in A53T-SNCA mice.NPJ Parkinson's disease · 2026Article
- A microfluidic platform for whole-membrane integrity profiling in live neuronal cells.Microsystems & nanoengineering · 2026Article
- Alpha-Synuclein in Neurodegeneration: From Shared Biology to Disease-Specific Phenotypes.Cells · 2026Review
- C-terminus-dependent detection of lysosomal alpha-synuclein in nigral Parkinson's disease human brain neurons.Molecular neurodegeneration · 2025Article
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Authors and funding
25 authors.
Funding
Abstract
Alpha-synuclein (aSyn) post-translational modifications (PTM), especially phosphorylation at serine 129 and C-terminal truncations, are highly enriched in Lewy bodies (LB), Lewy neurites, and other pathological aggregates in Parkinson's disease and synucleinopathies. However, the precise role of these PTM in pathology formation, neurodegeneration, and pathology spreading remains unclear. Here, we systematically investigated the role of post-fibrillization C-terminal aSyn truncations in regulating uptake, processing, seeding, and LB-like inclusion formation using a neuronal seeding model that recapitulates LB formation and neurodegeneration. We show that C-terminal cleavage of aSyn fibrils occurs rapidly post exogenous fibril internalization and during intracellular LB-like inclusion formation. Blocking cleavage of internalized fibrils does not affect seeding, but inhibiting enzymes such as calpains 1 and 2 alters LB-like inclusion formation. We show that C-terminal truncations, along with other PTMs, regulate fibril interactome remodeling, shortening, lateral association, and packing. These findings reveal distinct roles of C-terminal truncations at different aggregation stages on the pathway to LB formation, highlighting the need for consideration of stage‑specific strategies to target aSyn proteolytic cleavages.
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