{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T20:57:41Z","timestamp":1791493061525,"version":"4.3.4"},"reference-count":76,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2025,2,6]],"date-time":"2025-02-06T00:00:00Z","timestamp":1738800000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001866","name":"Fonds National de la Recherche Luxembourg","doi-asserted-by":"publisher","award":["C19\/BM\/13535609"],"award-info":[{"award-number":["C19\/BM\/13535609"]}],"id":[{"id":"10.13039\/501100001866","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001866","name":"Fonds National de la Recherche Luxembourg","doi-asserted-by":"publisher","award":["C17\/BM\/11676395"],"award-info":[{"award-number":["C17\/BM\/11676395"]}],"id":[{"id":"10.13039\/501100001866","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000864","name":"Michael J. Fox Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010661","name":"Horizon 2020","doi-asserted-by":"publisher","award":["C21\/BM\/15850547"],"award-info":[{"award-number":["C21\/BM\/15850547"]}],"id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010661","name":"Horizon 2020","doi-asserted-by":"publisher","award":["PRIDE\/14254520\/I2TRON"],"award-info":[{"award-number":["PRIDE\/14254520\/I2TRON"]}],"id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,10,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The complex and heterogeneous nature of Parkinson's disease (PD) is still not fully understood. However, increasing evidence supports mitochondrial impairment as a major driver of neurodegeneration. Miro1, a mitochondrial GTPase encoded by the RHOT1 gene, is involved in mitochondrial transport, mitophagy and mitochondrial calcium buffering, and is therefore essential for maintaining mitochondrial homeostasis. Recently, Miro1 has been linked genetically and pathophysiologically to PD, further supported by the identification of heterozygous variants of Miro1 in patients.<\/jats:p>\n                  <jats:p>Herein, we used patient-derived cellular models alongside knock-in mice to investigate Miro1-dependent pathophysiological processes and molecular mechanisms underlying neurodegeneration in PD.<\/jats:p>\n                  <jats:p>Experimental work performed in induced pluripotent stem cell (iPSC)-derived models, including midbrain organoids and dopaminergic neuronal cell cultures from a PD patient carrying the p.R272Q Miro1 mutation as well as healthy and isogenic controls, indicated that the p.R272Q Miro1 mutation leads to increased oxidative stress, disrupted mitochondrial bioenergetics and altered cellular metabolism. These changes were accompanied by increased \u03b1-synuclein levels and a significant reduction of dopaminergic neurons. Moreover, the p.R272Q Miro1 mutation\u2014located in the calcium-binding domain of the GTPase\u2014disrupted calcium homeostasis, resulting in calcium-dependent activation of calpain proteases and the subsequent cleavage of \u03b1-synuclein. Knock-in mice expressing p.R285Q Miro1 (the murine orthologue of the human p.R272Q mutation) displayed accumulation of phosphorylated \u03b1-synuclein in the striatum and a significant loss of dopaminergic neurons in the substantia nigra pars compacta, accompanied by behavioural alterations.<\/jats:p>\n                  <jats:p>These findings demonstrate that mutant Miro1 is sufficient to comprehensively model PD-relevant phenotypes in vitro and in vivo, reinforcing its pivotal role in PD pathogenesis.<\/jats:p>","DOI":"10.1093\/brain\/awaf051","type":"journal-article","created":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T15:22:12Z","timestamp":1738768932000},"page":"3607-3622","source":"Crossref","is-referenced-by-count":32,"title":["Parkinson\u2019s disease mutant Miro1 causes mitochondrial dysfunction and dopaminergic neuron loss"],"prefix":"10.1093","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8758-5424","authenticated-orcid":false,"given":"Axel","family":"Chemla","sequence":"first","affiliation":[{"name":"Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg , L-4362 Esch-sur-Alzette ,","place":["Luxembourg"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2398-5503","authenticated-orcid":false,"given":"Giuseppe","family":"Arena","sequence":"additional","affiliation":[{"name":"Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg , L-4362 Esch-sur-Alzette ,","place":["Luxembourg"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ginevra","family":"Sacripanti","sequence":"additional","affiliation":[{"name":"Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg , L-4362 Esch-sur-Alzette ,","place":["Luxembourg"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyriaki","family":"Barmpa","sequence":"additional","affiliation":[{"name":"Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg , L-4362 Esch-sur-Alzette ,","place":["Luxembourg"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3724-540X","authenticated-orcid":false,"given":"Alise","family":"Zagare","sequence":"additional","affiliation":[{"name":"Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg , L-4362 Esch-sur-Alzette ,","place":["Luxembourg"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Garcia","sequence":"additional","affiliation":[{"name":"Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg , L-4362 Esch-sur-Alzette ,","place":["Luxembourg"]},{"name":"Luxembourg Center of Neuropathology (LCNP), Laboratoire National de Sant\u00e9 , L-3555, Dudelange ,","place":["Luxembourg"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vyron","family":"Gorgogietas","sequence":"additional","affiliation":[{"name":"Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg , L-4362 Esch-sur-Alzette ,","place":["Luxembourg"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0450-9301","authenticated-orcid":false,"given":"Paul","family":"Antony","sequence":"additional","affiliation":[{"name":"Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg , L-4362 Esch-sur-Alzette ,","place":["Luxembourg"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7109-6802","authenticated-orcid":false,"given":"Jochen","family":"Ohnmacht","sequence":"additional","affiliation":[{"name":"Transversal Translational Medicine, Luxembourg Institute of Health (LIH) , L-1445 Strassen ,","place":["Luxembourg"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Baron","sequence":"additional","affiliation":[{"name":"Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg , L-4362 Esch-sur-Alzette ,","place":["Luxembourg"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaqueline","family":"Jung","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics and Applied Genomics, University of T\u00fcbingen , 72076 T\u00fcbingen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frida","family":"Lind-Holm Mogensen","sequence":"additional","affiliation":[{"name":"Faculty of Science, Technology and Medicine, University of Luxembourg , L-4365 Esch-sur-Alzette ,","place":["Luxembourg"]},{"name":"Department of Cancer Research, Luxembourg Institute of Health (LIH) , L-1210 Luxembourg 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Dudelange ,","place":["Luxembourg"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1862-655X","authenticated-orcid":false,"given":"Thorsten","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics and Applied Genomics, University of T\u00fcbingen , 72076 T\u00fcbingen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4179-2994","authenticated-orcid":false,"given":"Anne","family":"Gr\u00fcnewald","sequence":"additional","affiliation":[{"name":"Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg , L-4362 Esch-sur-Alzette ,","place":["Luxembourg"]},{"name":"Institute of Neurogenetics, University of L\u00fcbeck , 160 L\u00fcbeck ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4496-0559","authenticated-orcid":false,"given":"Jens C","family":"Schwamborn","sequence":"additional","affiliation":[{"name":"Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg , L-4362 Esch-sur-Alzette ,","place":["Luxembourg"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rejko","family":"Kr\u00fcger","sequence":"additional","affiliation":[{"name":"Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg , L-4362 Esch-sur-Alzette ,","place":["Luxembourg"]},{"name":"Transversal Translational Medicine, Luxembourg Institute of Health (LIH) , L-1445 Strassen ,","place":["Luxembourg"]},{"name":"Parkinson Research Clinic, Centre Hospitalier de Luxembourg , L-1210, Luxembourg ,","place":["Luxembourg"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4866-8790","authenticated-orcid":false,"given":"Cl\u00e1udia","family":"Saraiva","sequence":"additional","affiliation":[{"name":"Luxembourg Centre for Systems Biomedicine (LCSB), University of 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