Disrupting the α-synuclein-ESCRT interaction with a peptide inhibitor mitigates neurodegeneration in preclinical models of Parkinson’s disease
<p dir="ltr">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-synuclei...
Saved in:
| Main Author: | |
|---|---|
| Other Authors: | , , , , , , , , , , , , , , , , |
| Published: |
2023
|
| Subjects: | |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1864513507120119808 |
|---|---|
| author | Satra Nim (11540447) |
| author2 | Darren M. O’Hara (9201761) Carles Corbi-Verge (527968) Albert Perez-Riba (5004785) Kazuko Fujisawa (11692038) Minesh Kapadia (582056) Hien Chau (355945) Federica Albanese (19482364) Grishma Pawar (10666899) Mitchell L. De Snoo (19482367) Sophie G. Ngana (19482370) Jisun Kim (837555) Omar M. A. El-Agnaf (8809331) Enrico Rennella (2083291) Lewis E. Kay (135973) Suneil K. Kalia (9201773) Lorraine V. Kalia (9201770) Philip M. Kim (11540462) |
| author2_role | author author author author author author author author author author author author author author author author author |
| author_facet | Satra Nim (11540447) Darren M. O’Hara (9201761) Carles Corbi-Verge (527968) Albert Perez-Riba (5004785) Kazuko Fujisawa (11692038) Minesh Kapadia (582056) Hien Chau (355945) Federica Albanese (19482364) Grishma Pawar (10666899) Mitchell L. De Snoo (19482367) Sophie G. Ngana (19482370) Jisun Kim (837555) Omar M. A. El-Agnaf (8809331) Enrico Rennella (2083291) Lewis E. Kay (135973) Suneil K. Kalia (9201773) Lorraine V. Kalia (9201770) Philip M. Kim (11540462) |
| author_role | author |
| dc.creator.none.fl_str_mv | Satra Nim (11540447) Darren M. O’Hara (9201761) Carles Corbi-Verge (527968) Albert Perez-Riba (5004785) Kazuko Fujisawa (11692038) Minesh Kapadia (582056) Hien Chau (355945) Federica Albanese (19482364) Grishma Pawar (10666899) Mitchell L. De Snoo (19482367) Sophie G. Ngana (19482370) Jisun Kim (837555) Omar M. A. El-Agnaf (8809331) Enrico Rennella (2083291) Lewis E. Kay (135973) Suneil K. Kalia (9201773) Lorraine V. Kalia (9201770) Philip M. Kim (11540462) |
| dc.date.none.fl_str_mv | 2023-04-19T09:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1038/s41467-023-37464-2 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Disrupting_the_-synuclein-ESCRT_interaction_with_a_peptide_inhibitor_mitigates_neurodegeneration_in_preclinical_models_of_Parkinson_s_disease/26830174 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biomedical and clinical sciences Clinical sciences Neurosciences Pharmacology and pharmaceutical sciences α-Synuclein Parkinson’s Disease Toxic Oligomers Protein-Protein Interaction Inhibitors CHarged Multivesicular body Protein 2B (CHMP2B) Preclinical Models C. elegans Rat Models |
| dc.title.none.fl_str_mv | Disrupting the α-synuclein-ESCRT interaction with a peptide inhibitor mitigates neurodegeneration in preclinical models of Parkinson’s disease |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p dir="ltr">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.</p><h2>Other Information</h2><p dir="ltr">Published in: Nature Communications<br>License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1038/s41467-023-37464-2" target="_blank">https://dx.doi.org/10.1038/s41467-023-37464-2</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_693c559b6c9a6a71cb865763319f41a7 |
| identifier_str_mv | 10.1038/s41467-023-37464-2 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/26830174 |
| publishDate | 2023 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Disrupting the α-synuclein-ESCRT interaction with a peptide inhibitor mitigates neurodegeneration in preclinical models of Parkinson’s diseaseSatra Nim (11540447)Darren M. O’Hara (9201761)Carles Corbi-Verge (527968)Albert Perez-Riba (5004785)Kazuko Fujisawa (11692038)Minesh Kapadia (582056)Hien Chau (355945)Federica Albanese (19482364)Grishma Pawar (10666899)Mitchell L. De Snoo (19482367)Sophie G. Ngana (19482370)Jisun Kim (837555)Omar M. A. El-Agnaf (8809331)Enrico Rennella (2083291)Lewis E. Kay (135973)Suneil K. Kalia (9201773)Lorraine V. Kalia (9201770)Philip M. Kim (11540462)Biomedical and clinical sciencesClinical sciencesNeurosciencesPharmacology and pharmaceutical sciencesα-SynucleinParkinson’s DiseaseToxic OligomersProtein-Protein Interaction InhibitorsCHarged Multivesicular body Protein 2B (CHMP2B)Preclinical ModelsC. elegansRat Models<p dir="ltr">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.</p><h2>Other Information</h2><p dir="ltr">Published in: Nature Communications<br>License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1038/s41467-023-37464-2" target="_blank">https://dx.doi.org/10.1038/s41467-023-37464-2</a></p>2023-04-19T09:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1038/s41467-023-37464-2https://figshare.com/articles/journal_contribution/Disrupting_the_-synuclein-ESCRT_interaction_with_a_peptide_inhibitor_mitigates_neurodegeneration_in_preclinical_models_of_Parkinson_s_disease/26830174CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/268301742023-04-19T09:00:00Z |
| spellingShingle | Disrupting the α-synuclein-ESCRT interaction with a peptide inhibitor mitigates neurodegeneration in preclinical models of Parkinson’s disease Satra Nim (11540447) Biomedical and clinical sciences Clinical sciences Neurosciences Pharmacology and pharmaceutical sciences α-Synuclein Parkinson’s Disease Toxic Oligomers Protein-Protein Interaction Inhibitors CHarged Multivesicular body Protein 2B (CHMP2B) Preclinical Models C. elegans Rat Models |
| status_str | publishedVersion |
| title | Disrupting the α-synuclein-ESCRT interaction with a peptide inhibitor mitigates neurodegeneration in preclinical models of Parkinson’s disease |
| title_full | Disrupting the α-synuclein-ESCRT interaction with a peptide inhibitor mitigates neurodegeneration in preclinical models of Parkinson’s disease |
| title_fullStr | Disrupting the α-synuclein-ESCRT interaction with a peptide inhibitor mitigates neurodegeneration in preclinical models of Parkinson’s disease |
| title_full_unstemmed | Disrupting the α-synuclein-ESCRT interaction with a peptide inhibitor mitigates neurodegeneration in preclinical models of Parkinson’s disease |
| title_short | Disrupting the α-synuclein-ESCRT interaction with a peptide inhibitor mitigates neurodegeneration in preclinical models of Parkinson’s disease |
| title_sort | Disrupting the α-synuclein-ESCRT interaction with a peptide inhibitor mitigates neurodegeneration in preclinical models of Parkinson’s disease |
| topic | Biomedical and clinical sciences Clinical sciences Neurosciences Pharmacology and pharmaceutical sciences α-Synuclein Parkinson’s Disease Toxic Oligomers Protein-Protein Interaction Inhibitors CHarged Multivesicular body Protein 2B (CHMP2B) Preclinical Models C. elegans Rat Models |