| Autor: |
Nim, Satra, O'Hara, Darren M., Corbi-Verge, Carles, Perez-Riba, Albert, Fujisawa, Kazuko, Kapadia, Minesh, Chau, Hien, Albanese, Federica, Pawar, Grishma, De Snoo, Mitchell L., Ngana, Sophie G., Kim, Jisun, El-Agnaf, Omar M. A., Rennella, Enrico, Kay, Lewis E., Kalia, Suneil K., Kalia, Lorraine V., Kim, Philip M. |
| Předmět: |
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| Zdroj: |
Nature Communications; 4/19/2023, Vol. 14 Issue 1, p1-19, 19p |
| Abstrakt: |
Accumulation of α-synuclein into toxic oligomers or fibrils is implicated in dopaminergic neurodegeneration in Parkinson's disease. Here we performed a high-throughput, proteome-wide peptide screen to identify protein-protein interaction inhibitors that reduce α-synuclein oligomer levels and their associated cytotoxicity. We find that the most potent peptide inhibitor disrupts the direct interaction between the C-terminal region of α-synuclein and CHarged Multivesicular body Protein 2B (CHMP2B), a component of the Endosomal Sorting Complex Required for Transport-III (ESCRT-III). We show that α-synuclein impedes endolysosomal activity via this interaction, thereby inhibiting its own degradation. Conversely, the peptide inhibitor restores endolysosomal function and thereby decreases α-synuclein levels in multiple models, including female and male human cells harboring disease-causing α-synuclein mutations. Furthermore, the peptide inhibitor protects dopaminergic neurons from α-synuclein-mediated degeneration in hermaphroditic C. elegans and preclinical Parkinson's disease models using female rats. Thus, the α-synuclein-CHMP2B interaction is a potential therapeutic target for neurodegenerative disorders. ESCRT-III is involved in the endolysosomal system and disturbed in neurodegenerative diseases. Here the authors show that disruption of an interaction between ESCRT-III member CHMP2B and α-synuclein by a peptide inhibitor mitigates neurodegeneration in Parkinson's disease models. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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