{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T22:35:08Z","timestamp":1789770908402,"version":"4.0.1"},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"16","license":[{"start":{"date-parts":[[2021,5,17]],"date-time":"2021-05-17T00:00:00Z","timestamp":1621209600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,7,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Parkinson\u2019s disease (PD) is a neurodegenerative disease with movement disorders including resting tremor, rigidity, bradykinesia and postural instability. Recent studies have identified a new PD associated gene, TMEM230 (transmembrane protein 230). However, the pathological roles of TMEM230 and its variants are not fully understood. TMEM230 gene encodes two protein isoforms. Isoform2 is the major protein form (~95%) in human. In this study, we overexpress isoform2 TMEM230 variants (WT or PD-linked *184Wext*5 mutant) or knockdown endogenous protein in cultured SH-5Y5Y cells and mouse primary hippocampus neurons to study their pathological roles. We found that overexpression of WT and mutant TMEM230 or knockdown of endogenous TMEM230-induced neurodegeneration and impaired mitochondria transport at the retrograde direction in axons. Mutant TMEM230 caused more severe neurotoxicity and mitochondrial transport impairment than WT-TMEM230 did. Our results demonstrate that maintaining TMEM230 protein levels is critical for neuron survival and axon transport. These findings suggest that mutant-TMEM230-induced mitochondrial transport impairment could be the early event leading to neurite injury and neurodegeneration in PD development.<\/jats:p>","DOI":"10.1093\/hmg\/ddab128","type":"journal-article","created":{"date-parts":[[2021,5,15]],"date-time":"2021-05-15T19:08:50Z","timestamp":1621105730000},"page":"1535-1542","source":"Crossref","is-referenced-by-count":13,"title":["Mutant-TMEM230-induced neurodegeneration and impaired axonal mitochondrial transport"],"prefix":"10.1093","volume":"30","author":[{"given":"Xiaobo","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"},{"name":"Institute of Neuroscience, Soochow University School of Medicine, Suzhou, Jiangsu 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gongbo","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinru","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"},{"name":"Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Aebez","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaohui","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy and Cytoneurobiology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou, Jiangsu 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-Feng","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Neuroscience, Soochow University School of Medicine, Suzhou, Jiangsu 215123, China"},{"name":"Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher A","family":"Ross","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanli W","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,5,17]]},"reference":[{"key":"2021080317191698400_ref1","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/j.molmed.2006.09.007","article-title":"Understanding the molecular causes of Parkinson\u2019s disease","volume":"12","author":"Wood-Kaczmar","year":"2006","journal-title":"Trends Mol. Med."},{"key":"2021080317191698400_ref2","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1038\/ng.3589","article-title":"Identification of TMEM230 mutations in familial Parkinson\u2019s disease","volume":"48","author":"Deng","year":"2016","journal-title":"Nat. Genet."},{"key":"2021080317191698400_ref3","doi-asserted-by":"crossref","first-page":"167.e11","DOI":"10.1016\/j.neurobiolaging.2016.10.004","article-title":"Lack of evidence for a role of genetic variation in TMEM230 in the risk for Parkinson\u2019s disease in the Caucasian population","volume":"50","author":"Giri","year":"2017","journal-title":"Neurobiol. Aging"},{"key":"2021080317191698400_ref4","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1002\/mds.26900","article-title":"Mutations in TMEM230 are not a common cause of Parkinson\u2019s disease","volume":"32","author":"Quadri","year":"2017","journal-title":"Mov. Disord."},{"key":"2021080317191698400_ref5","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.neuroscience.2020.11.004","article-title":"Controversy of TMEM230 associated with Parkinson\u2019s disease","volume":"453","author":"Wang","year":"2020","journal-title":"Neuroscience"},{"key":"2021080317191698400_ref6","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1080\/19768354.2018.1453545","article-title":"Characterization of Parkinson\u2019s disease-related pathogenic TMEM230 mutants","volume":"22","author":"Nam","year":"2018","journal-title":"Animal Cells Syst. (Seoul)."},{"key":"2021080317191698400_ref7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fnagi.2020.00235","article-title":"Transmembrane protein 230 mediates a poly(ADP-ribose) Polymerase-1-linked apoptosis","volume":"12","author":"Wang","year":"2020","journal-title":"Front. Aging Neurosci."},{"key":"2021080317191698400_ref8","article-title":"The Parkinson\u2019s disease-linked protein TMEM230 is required for Rab8a-mediated secretory vesicle trafficking and retromer trafficking","volume":"26","author":"Kim","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"2021080317191698400_ref9","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1016\/j.tcb.2014.05.002","article-title":"Integrated regulation of motor-driven organelle transport by scaffolding proteins","volume":"24","author":"Fu","year":"2014","journal-title":"Trends Cell Biol."},{"key":"2021080317191698400_ref10","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.neuron.2014.10.019","article-title":"Axonal transport: cargo-specific mechanisms of motility and regulation","volume":"84","author":"Maday","year":"2014","journal-title":"Neuron"},{"key":"2021080317191698400_ref11","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1016\/j.bbadis.2006.04.002","article-title":"Axonal transport and neurodegenerative disease","volume":"1762","author":"Chevalier-Larsen","year":"2006","journal-title":"Biochim. Biophys. Acta"},{"key":"2021080317191698400_ref12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fnagi.2016.00337","article-title":"68 and FX2149 attenuate mutant LRRK2-R1441C-induced neural transport impairment","volume":"8","author":"Thomas","year":"2017","journal-title":"Front. Aging Neurosci."},{"key":"2021080317191698400_ref13","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/j.tins.2007.03.009","article-title":"Multiple hit hypotheses for dopamine neuron loss in Parkinson\u2019s disease","volume":"30","author":"Sulzer","year":"2007","journal-title":"Trends Neurosci."},{"key":"2021080317191698400_ref14","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1038\/nrn3156","article-title":"Mitochondrial transport in neurons: impact on synaptic homeostasis and neurodegeneration","volume":"13","author":"Sheng","year":"2012","journal-title":"Nat. Rev. Neurosci."},{"key":"2021080317191698400_ref15","doi-asserted-by":"crossref","first-page":"a011304","DOI":"10.1101\/cshperspect.a011304","article-title":"Mitochondrial trafficking in neurons","volume":"5","author":"Schwarz","year":"2013","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"2021080317191698400_ref16","doi-asserted-by":"crossref","first-page":"3343","DOI":"10.1016\/j.febslet.2015.09.021","article-title":"Autophagy and proteins involved in vesicular trafficking","volume":"589","author":"Amaya","year":"2015","journal-title":"FEBS Lett."},{"key":"2021080317191698400_ref17","first-page":"1","article-title":"\u03b1synuclein control of mitochondrial homeostasis in human-derived neurons is disrupted by mutations associated with Parkinson\u2019s disease","volume":"7","author":"Devoto","year":"2017","journal-title":"Sci. Rep."},{"key":"2021080317191698400_ref18","doi-asserted-by":"crossref","first-page":"5245","DOI":"10.1038\/ncomms6245","article-title":"Increasing microtubule acetylation rescues axonal transport and locomotor deficits caused by LRRK2 roc-COR domain mutations","volume":"5","author":"Godena","year":"2014","journal-title":"Nat. Commun."},{"key":"2021080317191698400_ref19","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1016\/j.cell.2011.10.018","article-title":"PINK1 and Parkin target miro for phosphorylation and degradation to arrest mitochondrial motility","volume":"147","author":"Wang","year":"2011","journal-title":"Cell"},{"key":"2021080317191698400_ref20","doi-asserted-by":"crossref","first-page":"7212","DOI":"10.1523\/JNEUROSCI.0711-11.2011","article-title":"The parkinsonian mimetic, MPP+, specifically impairs mitochondrial transport in dopamine axons","volume":"31","author":"Kim-Han","year":"2011","journal-title":"J. Neurosci."},{"key":"2021080317191698400_ref21","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/1750-1326-9-17","article-title":"The parkinsonian mimetic, 6-OHDA, impairs axonal transport in dopaminergic axons","volume":"9","author":"Lu","year":"2014","journal-title":"Mol. Neurodegener."},{"key":"2021080317191698400_ref22","doi-asserted-by":"crossref","first-page":"e1811","DOI":"10.1038\/cddis.2015.169","article-title":"Alpha-Synuclein affects neurite morphology, autophagy, vesicle transport and axonal degeneration in CNS neurons","volume":"6","author":"Koch","year":"2015","journal-title":"Cell Death Dis."},{"key":"2021080317191698400_ref23","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1016\/j.ajpath.2012.10.027","article-title":"Mutant LRRK2 elicits calcium imbalance and depletion of dendritic mitochondria in neurons","volume":"182","author":"Cherra","year":"2013","journal-title":"Am. J. Pathol."},{"key":"2021080317191698400_ref24","doi-asserted-by":"crossref","first-page":"4545","DOI":"10.1093\/hmg\/ddt301","article-title":"Inhibition of excessive mitochondrial fission reduced aberrant autophagy and neuronal damage caused by LRRK2 G2019S mutation","volume":"22","author":"Su","year":"2013","journal-title":"Hum. Mol. Genet."},{"key":"2021080317191698400_ref25","doi-asserted-by":"crossref","first-page":"e1368","DOI":"10.1038\/cddis.2014.320","article-title":"The LRRK2 inhibitor GSK2578215A induces protective autophagy in SH-SY5Y cells: involvement of Drp-1-mediated mitochondrial fission and mitochondrial-derived ROS signaling","volume":"5","author":"Saez-Atienzar","year":"2014","journal-title":"Cell Death Dis."},{"key":"2021080317191698400_ref26","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.bbadis.2014.11.009","article-title":"Threonine 56 phosphorylation of Bcl-2 is required for LRRK2 G2019S-induced mitochondrial depolarization and autophagy","volume":"1852","author":"Su","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"2021080317191698400_ref27","doi-asserted-by":"crossref","first-page":"eaaaw9997","DOI":"10.1126\/science.aaw9997","article-title":"Axonal transport: driving synaptic function","volume":"366","author":"Guedes-Dias","year":"2019","journal-title":"Science"},{"key":"2021080317191698400_ref28","first-page":"1","article-title":"Motor proteins","volume":"10","author":"Lee Sweeney","year":"2018","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"2021080317191698400_ref29","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1111\/cns.13122","article-title":"Mitochondrial transport serves as a mitochondrial quality control strategy in axons: implications for central nervous system disorders","volume":"25","author":"Zheng","year":"2019","journal-title":"CNS Neurosci. Ther."},{"key":"2021080317191698400_ref30","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1038\/nn1776","article-title":"Kinase activity of mutant LRRK2 mediates neuronal toxicity","volume":"9","author":"Smith","year":"2006","journal-title":"Nat. Neurosci."},{"key":"2021080317191698400_ref31","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1093\/hmg\/ddz271","article-title":"G2019S-LRRK2 mutation enhances MPTP-linked parkinsonism in mice","volume":"29","author":"Arbez","year":"2020","journal-title":"Hum. Mol. Genet."},{"key":"2021080317191698400_ref32","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/B978-0-12-391857-4.00009-4","article-title":"Methods for cell and particle tracking","volume":"504","author":"Meijering","year":"2012","journal-title":"Methods Enzymol."},{"key":"2021080317191698400_ref33","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1016\/j.celrep.2015.06.032","article-title":"Stress-induced CDK5 activation disrupts axonal transport via Lis1\/Ndel1\/dynein","volume":"12","author":"Klinman","year":"2015","journal-title":"Cell Rep."},{"key":"2021080317191698400_ref34","doi-asserted-by":"crossref","first-page":"2543","DOI":"10.1091\/mbc.e17-01-0068","article-title":"Dynein efficiently navigates the dendritic cytoskeleton to drive the retrograde trafficking of BDNF\/TrkB signaling endosomes","volume":"28","author":"Ayloo","year":"2017","journal-title":"Mol. Biol. Cell"},{"key":"2021080317191698400_ref35","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1016\/j.neuron.2016.10.003","article-title":"Activity-dependent regulation of distinct transport and cytoskeletal Remodeling functions of the dendritic kinesin KIF21B","volume":"92","author":"Ghiretti","year":"2016","journal-title":"Neuron"}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/hmg\/advance-article-pdf\/doi\/10.1093\/hmg\/ddab128\/38488033\/ddab128.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/hmg\/article-pdf\/30\/16\/1535\/39351910\/ddab128.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/hmg\/article-pdf\/30\/16\/1535\/39351910\/ddab128.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,8,3]],"date-time":"2021-08-03T18:02:42Z","timestamp":1628013762000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/30\/16\/1535\/6277040"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,17]]},"references-count":35,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2021,5,17]]},"published-print":{"date-parts":[[2021,7,28]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddab128","relation":{},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,8,15]]},"published":{"date-parts":[[2021,5,17]]}}}