{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T03:51:33Z","timestamp":1792036293527,"version":"4.4.0"},"reference-count":52,"publisher":"Wiley","issue":"57","license":[{"start":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T00:00:00Z","timestamp":1785456000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T00:00:00Z","timestamp":1785456000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82273913"],"award-info":[{"award-number":["82273913"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82173656 82373709"],"award-info":[{"award-number":["82173656 82373709"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82371274"],"award-info":[{"award-number":["82371274"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The transmembrane protein 175 (TMEM175) is a high\u2010risk gene for Parkinson's disease (PD) and encodes an ion channel in lysosomes. Many PD\u2010associated variants in TMEM175 lead to the loss of ion channel function. In this study, we identified the PD\u2010associated TMEM175\u2010L156P variant is a missense mutation with trafficking deficiency. Using imaging, biochemical, and whole\u2010endolysosomal electrophysiological approaches, we identified that L156P abolished the lysosomal expression of TMEM175; instead, it accumulates in the endoplasmic reticulum (ER). The cytosolic segment of the fourth transmembrane helix (TM4\u20101), where the L156 resides, determined the lysosomal localization of TMEM175. Having understood the structural basis, we evaluated wild\u2010type (WT) TMEM175 and pharmacological chaperones previously used in cystic fibrosis treatment. We elucidated that WT partially rescued the aberrant expression of L156P. Moreover, the chaperones substantially reduced the ER\u2010retained L156P and facilitated its trafficking to lysosomes. We further screened and identified a bifunctional chemical molecule that both corrected the trafficking defects and potentiated the ion channel function of L156P. Notably, the chemical\u2010restored L156P is functional, as it relieves the lysosomal over\u2010acidification. Conclusively, we establish the relationship between aberrant trafficking and pathogenesis in PD, demonstrating the potential of utilizing \u201cchaperone plus agonist\u201d bifunctional chemical molecules as personalized treatment for PD.<\/jats:p>","DOI":"10.1002\/advs.76738","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T12:52:37Z","timestamp":1785502357000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Trafficking Deficiency of TMEM175 Variants in Parkinson's Disease Pathogenesis and the Prospects of Precision Medicine"],"prefix":"10.1002","volume":"13","author":[{"given":"Ting","family":"Luo","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Sciences Guizhou Medical University  Guiyang China"},{"name":"Zhongshan Institute for Drug Discovery  Zhongshan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"He","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences Guizhou Medical University  Guiyang China"},{"name":"Zhongshan Institute for Drug Discovery  Zhongshan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuyao","family":"Li","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences Southern Medical University  Guangzhou China"},{"name":"Zhongshan Institute for Drug Discovery  Zhongshan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoyu","family":"Guan","sequence":"additional","affiliation":[{"name":"Department of neurology &amp; National Clinical Research Center for Geriatric Disorders Xiangya Hospital Central South University  Changsha China"},{"name":"Key Laboratory of Hunan Province in Neurodegenerative Disorders Xiangya Hospital Central South University  Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruili","family":"Cui","sequence":"additional","affiliation":[{"name":"College of Pharmacy Nanjing University of Chinese Medicine  Nanjing China"},{"name":"Zhongshan Institute for Drug Discovery  Zhongshan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Shi","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Materia Medica Chinese Academy of Sciences  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongwen","family":"Jiang","sequence":"additional","affiliation":[{"name":"College of Pharmacy Nanjing University of Chinese Medicine  Nanjing China"},{"name":"Zhongshan Institute for Drug Discovery  Zhongshan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyu","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Pharmacy Macau University of Science and Technology  Taipa Macau China"},{"name":"Zhongshan Institute for Drug Discovery  Zhongshan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan","family":"Li","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Materia Medica Chinese Academy of Sciences  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiyuan","family":"Li","sequence":"additional","affiliation":[{"name":"College of Pharmacy Nanjing University of Chinese Medicine  Nanjing China"},{"name":"Shanghai Institute of Materia Medica Chinese Academy of Sciences  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Hu","sequence":"additional","affiliation":[{"name":"Pharmacology Laboratory Zhongshan Hospital Guangzhou University of Chinese Medicine  Zhongshan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yupeng","family":"Zhou","sequence":"additional","affiliation":[{"name":"Zhongshan Institute for Drug Discovery  Zhongshan China"},{"name":"Shanghai Institute of Materia Medica Chinese Academy of Sciences  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2120-1576","authenticated-orcid":false,"given":"Beisha","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of neurology &amp; National Clinical Research Center for Geriatric Disorders Xiangya Hospital Central South University  Changsha China"},{"name":"Key Laboratory of Hunan Province in Neurodegenerative Disorders Xiangya Hospital Central South University  Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanyan","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences Guizhou Medical University  Guiyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8931-5508","authenticated-orcid":false,"given":"Zhaobing","family":"Gao","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Materia Medica Chinese Academy of Sciences  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhou","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Materia Medica Chinese Academy of Sciences  Shanghai China"},{"name":"School of Pharmacy Xinjiang Medical University  Urumqi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0031-5646","authenticated-orcid":false,"given":"Zhenhua","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of neurology &amp; National Clinical Research Center for Geriatric Disorders Xiangya Hospital Central South University  Changsha China"},{"name":"Key Laboratory of Hunan Province in Neurodegenerative Disorders Xiangya Hospital Central South University  Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1871-176X","authenticated-orcid":false,"given":"Ping","family":"Li","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences Guizhou Medical University  Guiyang China"},{"name":"School of Pharmaceutical Sciences Southern Medical University  Guangzhou China"},{"name":"College of Pharmacy Nanjing University of Chinese Medicine  Nanjing China"},{"name":"School of Pharmacy Macau University of Science and Technology  Taipa Macau China"},{"name":"Zhongshan Institute for Drug Discovery  Zhongshan China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,31]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00050.2006"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00025.2023"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-021014-071649"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2011.10.003"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M511765200"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms6535"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2004.01.022"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2018.10.006"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI169551"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M708735200"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-06115-2"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3955"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1616332114"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03185-z"},{"key":"e_1_2_11_16_1","doi-asserted-by":"crossref","first-page":"2292","DOI":"10.1016\/j.cell.2022.05.021","article-title":"Parkinson's Disease\u2010Risk Protein TMEM175 is a Proton\u2010Activated Proton Channel In Lysosomes","volume":"185","author":"Hu M.","journal-title":"Cell"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.3233\/JPD-212658"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abm1568"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/febs.16814"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.53683"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.53430"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature23269"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2023.06.004"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.08.002"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.75122"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2022.2125629"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-022-03203-9"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddz136"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25629"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2022.889057"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-021-00455-2"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41531-024-00853-5"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41531-023-00456-6"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2025.07.029"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aan6298"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature07311"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.1253"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a009761"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.12.009"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-42586-8"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1089\/adt.2009.0245"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.51423"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.72.121801.161800"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0854.2006.00387.x"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1202194109"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0408270101"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2014.01.035"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0709846104"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M306097200"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201812237"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd.2018.168"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-021-00371-6"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pharmtox-022123-104147"}],"container-title":["Advanced Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.76738","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/advs.76738","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.76738","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T03:31:59Z","timestamp":1792035119000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/advs.76738"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,31]]},"references-count":52,"journal-issue":{"issue":"57","published-print":{"date-parts":[[2026,10]]}},"alternative-id":["10.1002\/advs.76738"],"URL":"https:\/\/doi.org\/10.1002\/advs.76738","archive":["Portico"],"relation":{},"ISSN":["2198-3844","2198-3844"],"issn-type":[{"value":"2198-3844","type":"print"},{"value":"2198-3844","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,31]]},"assertion":[{"value":"2025-12-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-14","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-31","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e76738"}}