{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T05:03:17Z","timestamp":1788238997754,"version":"build-2803163510"},"reference-count":89,"publisher":"Oxford University Press (OUP)","issue":"22","license":[{"start":{"date-parts":[[2019,10,10]],"date-time":"2019-10-10T00:00:00Z","timestamp":1570665600000},"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":["ES007028"],"award-info":[{"award-number":["ES007028"]}],"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":["ES028084"],"award-info":[{"award-number":["ES028084"]}],"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":["ES016931"],"award-info":[{"award-number":["ES016931"]}],"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":["RO1 ES010563"],"award-info":[{"award-number":["RO1 ES010563"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,11,15]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The molecular etiology linking the pathogenic mutations in the Huntingtin (Htt) gene with Huntington\u2019s disease (HD) is unknown. Prior work suggests a role for Htt in neuronal autophagic function and mutant HTT protein disrupts autophagic cargo loading. Reductions in the bioavailability of the essential metal manganese (Mn) are seen in models of HD. Excess cellular Mn impacts autophagic function, but the target and molecular basis of these changes are unknown. Thus, we sought to determine if changes in cellular Mn status impact autophagic processes in a wild-type or mutant Htt-dependent manner. We report that the HD genotype is associated with reduced Mn-induced autophagy and that acute Mn exposure increases autophagosome induction\/formation. To determine if a deficit in bioavailable Mn is mechanistically linked to the autophagy-related HD cellular phenotypes, we examined autophagosomes by electron microscopy. We observed that a 24\u00a0h 100\u00a0uM Mn restoration treatment protocol attenuated an established HD \u2018cargo-recognition failure\u2019 in the STHdh HD model cells by increasing the percentage of filled autophagosomes. Mn restoration had no effect on HTT aggregate number, but a 72\u00a0h co-treatment with chloroquine (CQ) in GFP-72Q-expressing HEK293 cells increased the number of visible aggregates in a dose-dependent manner. As CQ prevents autophagic degradation this indicates that Mn restoration in HD cell models facilitates incorporation of aggregates into autophagosomes. Together, these findings suggest that defective Mn homeostasis in HD models is upstream of the impaired autophagic flux and provide proof-of-principle support for increasing bioavailable Mn in HD to restore autophagic function and promote aggregate clearance.<\/jats:p>","DOI":"10.1093\/hmg\/ddz209","type":"journal-article","created":{"date-parts":[[2019,9,19]],"date-time":"2019-09-19T19:27:32Z","timestamp":1568921252000},"page":"3825-3841","source":"Crossref","is-referenced-by-count":24,"title":["Acute manganese treatment restores defective autophagic cargo loading in Huntington\u2019s disease cell lines"],"prefix":"10.1093","volume":"28","author":[{"given":"Miles R","family":"Bryan","sequence":"first","affiliation":[{"name":"Department of Pediatrics"},{"name":"Vanderbilt Brain Institute"},{"name":"Department of Neurology and Biochemistry"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4580-2619","authenticated-orcid":false,"given":"Michael T","family":"O\u2019Brien","sequence":"first","affiliation":[{"name":"Department of Pediatrics"},{"name":"Vanderbilt Brain Institute"},{"name":"Department of Neurology and Biochemistry"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen D","family":"Nordham","sequence":"first","affiliation":[{"name":"Department of Pediatrics"},{"name":"Vanderbilt Brain Institute"},{"name":"Department of Neurology and Biochemistry"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel I R","family":"Rose","sequence":"first","affiliation":[{"name":"Department of Pediatrics"},{"name":"Vanderbilt Brain Institute"},{"name":"Department of Neurology and Biochemistry"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audra M","family":"Foshage","sequence":"first","affiliation":[{"name":"Department of Cell and Developmental Biology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piyush","family":"Joshi","sequence":"first","affiliation":[{"name":"Department of Pediatrics"},{"name":"Vanderbilt Brain Institute"},{"name":"Department of Neurology and Biochemistry"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachana","family":"Nitin","sequence":"first","affiliation":[{"name":"Department of Pediatrics"},{"name":"Vanderbilt Brain Institute"},{"name":"Department of Neurology and Biochemistry"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A","family":"Uhouse","sequence":"first","affiliation":[{"name":"Department of Pediatrics"},{"name":"Vanderbilt Brain Institute"},{"name":"Department of Neurology and Biochemistry"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alba","family":"Di Pardo","sequence":"first","affiliation":[{"name":"IRCCS Neuromed, Pozzilli (IS), 86077, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyan","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vittorio","family":"Maglione","sequence":"first","affiliation":[{"name":"IRCCS Neuromed, Pozzilli (IS), 86077, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Aschner","sequence":"first","affiliation":[{"name":"Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8728-3346","authenticated-orcid":false,"given":"Aaron B","family":"Bowman","sequence":"first","affiliation":[{"name":"Department of Pediatrics"},{"name":"Vanderbilt Brain Institute"},{"name":"Department of Neurology and Biochemistry"},{"name":"Department of Cell and Developmental Biology"},{"name":"Vanderbilt Kennedy Center"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,10,10]]},"reference":[{"key":"2020062013032733600_ref1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2011.112","article-title":"Neurodegenerative processes in Huntington's disease","volume":"2","author":"Bano","year":"2011","journal-title":"Cell Death Dis."},{"key":"2020062013032733600_ref2","article-title":"Huntington's disease","author":"Bates","year":"2014","journal-title":"Huntington's disease."},{"key":"2020062013032733600_ref3","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.gene.2014.11.022","article-title":"Huntington's disease: an update of therapeutic strategies","volume":"556","author":"Kumar","year":"2015","journal-title":"Gene"},{"key":"2020062013032733600_ref4","doi-asserted-by":"publisher","first-page":"520","DOI":"10.1016\/j.mam.2006.08.008","article-title":"Role of autophagy in the clearance of mutant huntingtin: a step towards therapy?","volume":"27","author":"Ravikumar","year":"2006","journal-title":"Mol. 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