{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T08:29:40Z","timestamp":1772267380837,"version":"3.50.1"},"reference-count":117,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T00:00:00Z","timestamp":1621296000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"},{"start":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T00:00:00Z","timestamp":1621296000000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"},{"start":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T00:00:00Z","timestamp":1621296000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/100000026","name":"National Institute on Drug Abuse","doi-asserted-by":"publisher","award":["R01-DA038058"],"award-info":[{"award-number":["R01-DA038058"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000026","name":"National Institute on Drug Abuse","doi-asserted-by":"publisher","award":["R01-DA035263"],"award-info":[{"award-number":["R01-DA035263"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"publisher","award":["F31-MH114316"],"award-info":[{"award-number":["F31-MH114316"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["P41-GM103712"],"award-info":[{"award-number":["P41-GM103712"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000026","name":"National Institute on Drug Abuse","doi-asserted-by":"publisher","award":["P30-DA035778"],"award-info":[{"award-number":["P30-DA035778"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000026","name":"National Institute on Drug Abuse","doi-asserted-by":"publisher","award":["Z1A DA000606"],"award-info":[{"award-number":["Z1A DA000606"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elifesciences.org"],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>\n                    Parkinson disease (PD) is a progressive, neurodegenerative disorder affecting over 6.1 million people worldwide. Although the cause of PD remains unclear, studies of highly penetrant mutations identified in early-onset familial parkinsonism have contributed to our understanding of the molecular mechanisms underlying disease pathology. Dopamine (DA) transporter (DAT) deficiency syndrome (DTDS) is a distinct type of infantile parkinsonism-dystonia that shares key clinical features with PD, including motor deficits (progressive bradykinesia, tremor, hypomimia) and altered DA neurotransmission. Here, we define structural, functional, and behavioral consequences of a Cys substitution at R445 in human DAT (hDAT R445C), identified in a patient with DTDS. We found that this R445 substitution disrupts a phylogenetically conserved intracellular (IC) network of interactions that compromise the hDAT IC gate. This is demonstrated by both Rosetta molecular modeling and fine-grained simulations using hDAT R445C, as well as EPR analysis and X-ray crystallography of the bacterial homolog leucine transporter. Notably, the disruption of this IC network of interactions supported a channel-like intermediate of hDAT and compromised hDAT function. We demonstrate that\n                    <jats:italic>Drosophila melanogaster<\/jats:italic>\n                    expressing hDAT R445C show impaired hDAT activity, which is associated with DA dysfunction in isolated brains and with abnormal behaviors monitored at high-speed time resolution. We show that hDAT R445C\n                    <jats:italic>Drosophila<\/jats:italic>\n                    exhibit motor deficits, lack of motor coordination (i.e. flight coordination) and phenotypic heterogeneity in these behaviors that is typically associated with DTDS and PD. These behaviors are linked with altered dopaminergic signaling stemming from loss of DA neurons and decreased DA availability. We rescued flight coordination with chloroquine, a lysosomal inhibitor that enhanced DAT expression in a heterologous expression system. Together, these studies shed some light on how a DTDS-linked DAT mutation underlies DA dysfunction and, possibly, clinical phenotypes shared by DTDS and PD.\n                  <\/jats:p>","DOI":"10.7554\/elife.68039","type":"journal-article","created":{"date-parts":[[2021,5,17]],"date-time":"2021-05-17T20:00:15Z","timestamp":1621281615000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.68039","source":"Crossref","is-referenced-by-count":23,"title":["Psychomotor impairments and therapeutic implications revealed by a mutation associated with infantile Parkinsonism-Dystonia"],"prefix":"10.7554","volume":"10","author":[{"given":"Jenny I","family":"Aguilar","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Vanderbilt University, Nashville, United States"},{"name":"Department of Surgery, University of Alabama at Birmingham, Birmingham, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mary Hongying","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5284-1344","authenticated-orcid":true,"given":"Josep","family":"Font","sequence":"additional","affiliation":[{"name":"School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7846-3772","authenticated-orcid":true,"given":"Alexandra C","family":"Schwartz","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaitlyn","family":"Ledwitch","sequence":"additional","affiliation":[{"name":"Center for Structural Biology, Vanderbilt University, Nashville, United States"},{"name":"Department of Chemistry, Vanderbilt University, Nashville, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda","family":"Duran","sequence":"additional","affiliation":[{"name":"Center for Structural Biology, Vanderbilt University, Nashville, United States"},{"name":"Department of Chemistry, Vanderbilt University, Nashville, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel J","family":"Mabry","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Alabama at Birmingham, Birmingham, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea N","family":"Belovich","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Idaho College of Osteopathic Medicine, Meridian, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanqi","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Alabama at Birmingham, Birmingham, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5766-3743","authenticated-orcid":true,"given":"Angela M","family":"Carter","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Alabama at Birmingham, Birmingham, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4137-096X","authenticated-orcid":true,"given":"Lei","family":"Shi","sequence":"additional","affiliation":[{"name":"Computational Chemistry and Molecular Biophysics Section, NIDA, NIH, Baltimore, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manju A","family":"Kurian","sequence":"additional","affiliation":[{"name":"Molecular Neurosciences, Developmental Neurosciences, University College London (UCL), London, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Fenollar-Ferrer","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular & Cellular Neurobiology, NIMH, NIH, Bethesda, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jens","family":"Meiler","sequence":"additional","affiliation":[{"name":"Center for Structural Biology, Vanderbilt University, Nashville, United States"},{"name":"Department of Chemistry, Vanderbilt University, Nashville, United States"},{"name":"Institute for Drug Discovery, Leipzig University Medical School, Leipzig, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Renae Monique","family":"Ryan","sequence":"additional","affiliation":[{"name":"School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hassane S","family":"Mchaourab","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9959-4176","authenticated-orcid":true,"given":"Ivet","family":"Bahar","sequence":"additional","affiliation":[{"name":"Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3615-7571","authenticated-orcid":true,"given":"Heinrich JG","family":"Matthies","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Alabama at Birmingham, Birmingham, United 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