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Disrupting the α-synuclein-ESCRT interaction with a peptide inhibitor mitigates neurodegeneration in preclinical models of Parkinson's disease

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

Nature communications, 2023-04, Vol.14 (1), p.2150-2150, Article 2150 [Periódico revisado por pares]

England: Nature Publishing Group

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Título:
Disrupting the α-synuclein-ESCRT interaction with a peptide inhibitor mitigates neurodegeneration in preclinical models of Parkinson's disease
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
Assuntos: alpha-Synuclein - genetics ; alpha-Synuclein - metabolism ; Animal models ; Animals ; Caenorhabditis elegans - metabolism ; Cytotoxicity ; Degeneration ; Disruption ; Dopamine receptors ; Dopaminergic Neurons - metabolism ; Endosomal Sorting Complexes Required for Transport - metabolism ; Female ; Females ; Fibrils ; Hermaphroditism ; Humans ; Inhibitors ; Male ; Movement disorders ; Neurodegeneration ; Neurodegenerative diseases ; Oligomers ; Parkinson Disease - drug therapy ; Parkinson Disease - metabolism ; Parkinson's disease ; Peptide inhibitors ; Peptides ; Peptides - metabolism ; Peptides - pharmacology ; Protein interaction ; Proteins ; Proteomes ; Rats ; Synuclein ; Therapeutic targets ; Toxicity
É parte de: Nature communications, 2023-04, Vol.14 (1), p.2150-2150, Article 2150
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Descrição: 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.
Editor: England: Nature Publishing Group
Idioma: Inglês

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Disrupting the α-synuclein-ESCRT interaction with a peptide inhibitor mitigates neurodegeneration in preclinical models of Parkinson's disease

England: Nature Publishing Group

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