{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T02:50:50Z","timestamp":1788058250926,"version":"build-2784847793"},"reference-count":52,"publisher":"SAGE Publications","issue":"8","license":[{"start":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T00:00:00Z","timestamp":1729123200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T00:00:00Z","timestamp":1729123200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01NS121294"],"award-info":[{"award-number":["R01NS121294"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["Supplement to R01NS121294"],"award-info":[{"award-number":["Supplement to R01NS121294"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R21NS127002"],"award-info":[{"award-number":["R21NS127002"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Parkinson\u2019s Disease"],"published-print":{"date-parts":[[2024,12]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Multiple system atrophy (MSA) and Parkinson's disease (PD) are caused by misfolded \u03b1-synuclein spreading throughout the central nervous system. While familial PD is linked to several \u03b1-synuclein mutations, no mutations are associated with MSA. We previously showed that the familial PD mutation E46K inhibits replication of MSA prions both\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      , providing key evidence to support the hypothesis that \u03b1-synuclein adopts unique strains in patients.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Here we sought to further interrogate \u03b1-synuclein misfolding to identify the structural determinants that contribute to MSA strain biology.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We engineered a panel of cell lines harbouring both PD-linked and novel mutations designed to identify key residues that facilitate \u03b1-synuclein misfolding in MSA. We also used Maestro\n                      <jats:italic toggle=\"yes\">in silico<\/jats:italic>\n                      analyses to predict the effect of each mutation on \u03b1-synuclein misfolding into one of the reported MSA cryo-electron microscopy conformations.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In many cases, our modelling accurately identified mutations that facilitated or inhibited MSA replication. However, Maestro was occasionally unable to predict the effect of a mutation, demonstrating the challenge of using computational tools to investigate intrinsically disordered proteins. Finally, we used our cellular models to determine the mechanism underlying the E46K-driven inhibition of MSA replication, finding that the E46\/K80 salt bridge is necessary to support \u03b1-synuclein misfolding.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our studies used a structure-based approach to investigate \u03b1-synuclein misfolding, resulting in the creation of a powerful panel of cell lines that can be used to interrogate MSA strain biology.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3233\/jpd-240296","type":"journal-article","created":{"date-parts":[[2024,11,26]],"date-time":"2024-11-26T09:12:15Z","timestamp":1732612335000},"page":"1543-1558","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":7,"title":["Structurally targeted mutagenesis identifies key residues supporting \u03b1-synuclein misfolding in multiple system atrophy"],"prefix":"10.1177","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9803-1304","authenticated-orcid":false,"given":"Patricia M","family":"Reis","sequence":"first","affiliation":[{"name":"Department of Biology and Institute for Applied Life Sciences, University of Massachusetts Amherst, Amherst, MA, USA"},{"name":"Neuroscience and Behavior Graduate Program, University of Massachusetts Amherst, Amherst, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0800-1115","authenticated-orcid":false,"given":"Sara AM","family":"Holec","sequence":"additional","affiliation":[{"name":"Department of Biology and Institute for Applied Life Sciences, University of Massachusetts Amherst, Amherst, MA, USA"},{"name":"Department of Microbiology, Immunology, and Pathology, Prion Research Center, Colorado State University, Fort Collins, CO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3395-2881","authenticated-orcid":false,"given":"Chimere","family":"Ezeiruaku","sequence":"additional","affiliation":[{"name":"Department of Biology and Institute for Applied Life Sciences, University of Massachusetts Amherst, Amherst, MA, USA"},{"name":"Current affiliation: Department of Surgery, Division of Abdominal Transplant Surgery, Stanford University School of Medicine, Palo Alto, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9973-2572","authenticated-orcid":false,"given":"Matthew P","family":"Frost","sequence":"additional","affiliation":[{"name":"Department of Biology and Institute for Applied Life Sciences, University of Massachusetts Amherst, Amherst, MA, USA"},{"name":"Current affiliation: Neuroscience Department, UConn Health, Farmington, CT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8771-3713","authenticated-orcid":false,"given":"Christine K","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of Biology and Institute for Applied Life Sciences, University of Massachusetts Amherst, Amherst, MA, USA"},{"name":"Current affiliation: Department of Biomedical Engineering, University of Massachusetts Amherst, Amherst, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3692-0879","authenticated-orcid":false,"given":"Samantha L","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Biology and Institute for Applied Life Sciences, University of Massachusetts Amherst, Amherst, MA, USA"},{"name":"Current affiliation: Department of Biochemistry and Cell Biology, Dartmouth College, Hanover, NH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven H","family":"Olson","sequence":"additional","affiliation":[{"name":"Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4029-1968","authenticated-orcid":false,"given":"Amanda L.","family":"Woerman","sequence":"additional","affiliation":[{"name":"Department of Biology and Institute for Applied Life Sciences, University of Massachusetts Amherst, Amherst, MA, USA"},{"name":"Department of Microbiology, Immunology, and Pathology, Prion Research Center, Colorado State University, Fort Collins, CO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2024,10,17]]},"reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/mds.26424"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/mds.29005"},{"key":"e_1_3_5_4_2","first-page":"920","volume-title":"Pathologische Anatomie Handbuch der Neurologie","author":"Forster E","year":"1912","unstructured":"Forster E, Lewy FH. 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