Sequestration of synaptic proteins by alpha-synuclein aggregates leading to neurotoxicity is inhibited by small peptide.

?-Synuclein (?-syn) is a major component of Lewy bodies found in synucleinopathies including Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB). Under the pathological conditions, ?-syn tends to generate a diverse form of aggregates showing toxicity to neuronal cells and able to transmit across cells. However, mechanisms by which ...
?-syn aggregates affect cytotoxicity in neurons have not been fully elucidated. Here we report that ?-syn aggregates preferentially sequester specific synaptic proteins such as vesicle-associated membrane protein 2 (VAMP2) and synaptosomal-associated protein 25 (SNAP25) through direct binding which is resistant to SDS. The sequestration effect of ?-syn aggregates was shown in a cell-free system, cultured primary neurons, and PD mouse model. Furthermore, we identified a specific blocking peptide derived from VAMP2 which partially inhibited the sequestration by ?-syn aggregates and contributed to reduced neurotoxicity. These results provide a mechanism of neurotoxicity mediated by ?-syn aggregates and suggest that the blocking peptide interfering with the pathological role of ?-syn aggregates could be useful for designing a potential therapeutic drug for the treatment of PD.
Mesh Terms:
Amyloid beta-Peptides, Animals, Brain, Cell Survival, Cells, Cultured, Disease Models, Animal, Escherichia coli, Humans, Mice, Inbred C3H, Mice, Inbred C57BL, Microscopy, Electron, Transmission, Neurons, Neuroprotective Agents, Parkinson Disease, Peptides, Protein Aggregation, Pathological, Protein Binding, Rats, Sprague-Dawley, Recombinant Proteins, Vesicle-Associated Membrane Protein 2, alpha-Synuclein
PLoS One
Date: Apr. 03, 2018
Download Curated Data For This Publication
231446
Switch View:
  • Interactions 2