{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T09:36:24Z","timestamp":1790760984892,"version":"4.1.0"},"reference-count":101,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2022,1,1]],"date-time":"2022-01-01T00:00:00Z","timestamp":1640995200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01NS089737"],"award-info":[{"award-number":["R01NS089737"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01GM135326"],"award-info":[{"award-number":["R01GM135326"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21NS102780 (to Q.C.)"],"award-info":[{"award-number":["R21NS102780 (to Q.C.)"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21HD091512"],"award-info":[{"award-number":["R21HD091512"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01NS102382 (to P.J.)"],"award-info":[{"award-number":["R01NS102382 (to P.J.)"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01DC015000 (to K.K.)"],"award-info":[{"award-number":["R01DC015000 (to K.K.)"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01NS089737"],"award-info":[{"award-number":["R01NS089737"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NSF IOS-1845355 (to D.J.M.)"],"award-info":[{"award-number":["NSF IOS-1845355 (to D.J.M.)"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,3,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Mitochondrial defects are a hallmark of early pathophysiology in Alzheimer\u2019s disease, with pathologically phosphorylated tau reported to induce mitochondrial toxicity. Mitophagy constitutes a key pathway in mitochondrial quality control by which damaged mitochondria are targeted for autophagy. However, few details are known regarding the intersection of mitophagy and pathologies in tauopathy.<\/jats:p>\n               <jats:p>Here, by applying biochemical and cell biological approaches including time-lapse confocal imaging in live tauopathy neurons, combined with gene rescue experiments via stereotactic injections of adeno-associated virus particles into tauopathy mouse brains, electrophysiological recordings and behavioural tests, we demonstrate for the first time that mitochondrial distribution deficits at presynaptic terminals are an early pathological feature in tauopathy brains. Furthermore, Parkin-mediated mitophagy is extensively activated in tauopathy neurons, which accelerates mitochondrial Rho GTPase 1 (Miro1) turnover and consequently halts Miro1-mediated mitochondrial anterograde movement towards synaptic terminals. As a result, mitochondrial supply at tauopathy synapses is disrupted, impairing synaptic function. Strikingly, increasing Miro1 levels restores the synaptic mitochondrial population by enhancing mitochondrial anterograde movement and thus reverses tauopathy-associated synaptic failure. In tauopathy mouse brains, overexpression of Miro1 markedly elevates synaptic distribution of mitochondria and protects against synaptic damage and neurodegeneration, thereby counteracting impairments in learning and memory as well as synaptic plasticity.<\/jats:p>\n               <jats:p>Taken together, our study reveals that activation of the Parkin pathway triggers an unexpected effect\u2014depletion of mitochondria from synaptic terminals, a characteristic feature of early tauopathy. We further provide new mechanistic insights into how parkin activation-enhanced Miro1 degradation and impaired mitochondrial anterograde transport drive tauopathy-linked synaptic pathogenesis and establish a foundation for future investigations into new therapeutic strategies to prevent synaptic deterioration in Alzheimer\u2019s disease and other tauopathies.<\/jats:p>","DOI":"10.1093\/brain\/awab243","type":"journal-article","created":{"date-parts":[[2021,6,25]],"date-time":"2021-06-25T19:13:06Z","timestamp":1624648386000},"page":"305-323","source":"Crossref","is-referenced-by-count":41,"title":["Broad activation of the Parkin pathway induces synaptic mitochondrial deficits in early tauopathy"],"prefix":"10.1093","volume":"145","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6786-9980","authenticated-orcid":false,"given":"Yu Young","family":"Jeong","sequence":"first","affiliation":[{"name":"Division of Life Science, Department of Cell Biology and Neuroscience, School of Arts and Sciences, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sinsuk","family":"Han","sequence":"additional","affiliation":[{"name":"Division of Life Science, Department of Cell Biology and Neuroscience, School of Arts and Sciences, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nuo","family":"Jia","sequence":"additional","affiliation":[{"name":"Division of Life Science, Department of Cell Biology and Neuroscience, School of Arts and Sciences, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Life Science, Department of Cell Biology and Neuroscience, School of Arts and Sciences, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Preethi","family":"Sheshadri","sequence":"additional","affiliation":[{"name":"Division of Life Science, Department of Cell Biology and Neuroscience, School of Arts and Sciences, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prasad","family":"Tammineni","sequence":"additional","affiliation":[{"name":"Division of Life Science, Department of Cell Biology and Neuroscience, School of Arts and Sciences, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmine","family":"Cheung","sequence":"additional","affiliation":[{"name":"Division of Life Science, Department of Cell Biology and Neuroscience, School of Arts and Sciences, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, 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J","family":"Margolis","sequence":"additional","affiliation":[{"name":"Division of Life Science, Department of Cell Biology and Neuroscience, School of Arts and Sciences, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Jiang","sequence":"additional","affiliation":[{"name":"Division of Life Science, Department of Cell Biology and Neuroscience, School of Arts and Sciences, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander W.","family":"Kusnecov","sequence":"additional","affiliation":[{"name":"Department of Psychology, School of Arts and Sciences, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, 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