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

Abstract

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.

Protein structure–function continuum model: Emerging nexuses between specificity, evolution, and structure

“…The recent results on disruption of the complex formation between α‐synuclein and Endosomal Sorting Complex Required for Transport (ESCORT) by a synthetic peptide show the spin‐off of not restricting ourselves to structure–function paradigm but viewing function from the window of continuum model (Nim et al, 2023). Multiple results over the years show that the focus on disorder, while designing proteins and their inhibitors pays dividends (Blundell et al, 2020; Gupta et al, 2020; Gupta & Roy, 2021; Protasova et al, 1994; Uversky et al, 1996).…”

Nuclear pore dysfunction and disease: a complex opportunity

“…The ESCRT-III pathway may also be a therapeutic target in PD. Recently, by screening a peptide library to find candidate molecules that prevent α-synuclein oligomerization, researchers discovered a novel interaction between α-synuclein and CHMP2B [ 341 ]. They showed that α-synuclein binds CHMP2B, leading to endolysosomal dysfunction [ 341 ].…”

“…Recently, by screening a peptide library to find candidate molecules that prevent α-synuclein oligomerization, researchers discovered a novel interaction between α-synuclein and CHMP2B [ 341 ]. They showed that α-synuclein binds CHMP2B, leading to endolysosomal dysfunction [ 341 ]. By abrogating this interaction, the researchers were able to reduce α-synuclein levels, restore autophagic degradation, and preserve cell viability [ 341 ].…”

Elegant Nematodes Improve Our Understanding of Human Neuronal Diseases, the Role of Pollutants and Strategies of Resilience

“…As part of the workflow, the candidate compounds were validated in C. elegans PD models. 34,35 Likewise, a C. elegans model for sporadic Creutzfeld-Jakob disease was developed and applied for the screening of antiprion drugs. 36 The concept of using C. elegans models of neurodegenerative aggregation diseases for high throughput applications is expandable to safety screening protocols of chemical compounds such as nanomaterials 37 and neurotoxicants.…”

“…Compound screening identified drug candidates for treatment of PD such as protein–protein interaction inhibitors that reduce amyloid aggregation of alpha synuclein and its cytotoxicity. As part of the workflow, the candidate compounds were validated in C. elegans PD models. , Likewise, a C. elegans model for sporadic Creutzfeld-Jakob disease was developed and applied for the screening of antiprion drugs …”