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Selective degradation of accumulated \u03b1Syn through ER-phagy can alleviate ER stress and rescue neurodegeneration. In the present study, we investigated whether mesenchymal stem cells (MSCs) exert neuroprotective effects against PD by modulating ER-phagy. In a cellular model overexpressing \u03b1Syn specifically in the ER (ER-\u03b1Syn), co-culture with MSCs promoted ER-\u03b1Syn clearance through selective ER-phagy and also recovered cell viability. Injection of MSCs to an animal model using adeno-associated virus vectors to overexpress \u03b1Syn in the ER (AAV-ER- \u03b1Syn), also decreased the expression of aSyn in the ER and attenuated the dopaminergic neuronal loss in substantia nigra (SN) and denervation in striatum (ST), followed by functional improvement of motor deficits. In vitro screening identified that MSCs promoted family with sequence similarity 134 member B (FAM134B)-mediated ER-phagy via regulating transcription factor of nuclear subfamily 4 group A member 1 (NR4A1), and it underwent in vivo validation. This study suggests that MSCs modulate FAM134B-mediated ER-phagy under the regulation of NR4A1, promoting the clearance of ER-accumulated \u03b1Syn in PD cellular and murine models.<\/jats:p>","DOI":"10.1093\/stcltm\/szaf019","type":"journal-article","created":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T07:41:34Z","timestamp":1745826094000},"source":"Crossref","is-referenced-by-count":8,"title":["Mesenchymal stem cells enhance selective ER-phagy to promote \u03b1-synuclein clearance in Parkinson\u2019s disease"],"prefix":"10.1093","volume":"14","author":[{"given":"Ji Eun","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Neurology, Yonsei University College of Medicine , Seoul 03722 ,","place":["South Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyu Won","family":"Oh","sequence":"additional","affiliation":[{"name":"Department of Neurology, Yonsei University College of Medicine , Seoul 03722 ,","place":["South Korea"]},{"name":"Department of Biomedical Sciences, Neuroscience Research Institute, Seoul National University College of Medicine , Seoul 03080 ,","place":["South Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin Young","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Neurology, Yonsei University College of Medicine , Seoul 03722 ,","place":["South Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeon Ju","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Neurology, Yonsei University College of Medicine , Seoul 03722 ,","place":["South Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5155-5335","authenticated-orcid":false,"given":"Seung-Jae","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Neuroscience Research Institute, Seoul National University College of Medicine , Seoul 03080 ,","place":["South Korea"]},{"name":"Convergence Research Center for Dementia, Seoul National University College of Medicine , Seoul 03081 ,","place":["Korea"]},{"name":"Neuramedy Co. 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