{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:47:09Z","timestamp":1792806429998,"version":"4.5.0"},"reference-count":71,"publisher":"National Academy of Sciences","issue":"12","license":[{"start":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T00:00:00Z","timestamp":1773619200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100014013","name":"UK Research and Innovation","doi-asserted-by":"publisher","award":["10059436"],"award-info":[{"award-number":["10059436"]}],"id":[{"id":"10.13039\/100014013","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014013","name":"UK Research and Innovation","doi-asserted-by":"publisher","award":["10061100"],"award-info":[{"award-number":["10061100"]}],"id":[{"id":"10.13039\/100014013","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,3,24]]},"abstract":"<jats:p>\n                    Parkinson\u2019s disease (PD) is a debilitating neurodegenerative condition that results in a loss of mobility and muscle control. A neuropathological hallmark of PD is the presence of aberrant inclusions, known as Lewy pathology, of which \u03b1-synuclein (\u03b1-Syn) is a major component. The accumulation of \u03b1-Syn may be due to an imbalance in the proteostasis system regulating \u03b1-Syn. To investigate this hypothesis, we delineated the proteostasis network (PN) of \u03b1-Syn in the human\n                    <jats:italic toggle=\"yes\">substantia nigra<\/jats:italic>\n                    at the proteomic and transcriptomic level. We then defined an \u03b1-Syn proteostasis activity score (PAS) that quantifiably describes the relative activity of the \u03b1-Syn PN in promoting or inhibiting \u03b1-Syn aggregation. We report a corresponding PAS signature indicative of disease state, age-of-death in PD patients, and brain regional vulnerability to \u03b1-Syn aggregation in PD and healthy brains. After establishing the relevance of our network to PD, we developed a transcriptome-derived network model as an operational digital twin of the \u03b1-Syn PN in human\n                    <jats:italic toggle=\"yes\">substantia nigra<\/jats:italic>\n                    cells from single-cell data and used it to prioritize candidate targets for PD. We then further showed the application of the \u03b1-Syn PN toward facilitating drug repurposing. Overall, this proof-of-concept study illustrates how our computational framework can identify and prioritize putative therapeutic targets and repurposing candidates for PD, providing testable hypotheses for experimental validation.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2513317123","type":"journal-article","created":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T19:06:28Z","timestamp":1773687988000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":4,"title":["The \u03b1-synuclein proteostasis network and its translational applications in Parkinson\u2019s disease"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5169-6672","authenticated-orcid":false,"given":"Christine M.","family":"Lim","sequence":"first","affiliation":[{"name":"Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge","place":["Cambridge, United 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