Lee Ji Eun, Oh Kyu Won, Shin Jin Young, Kim Yeon Ju, Lee Seung-Jae, Lee Phil Hyu
Department of Neurology, Yonsei University College of Medicine, Seoul 03722, South Korea.
Department of Biomedical Sciences, Neuroscience Research Institute, Seoul National University College of Medicine, Seoul 03080, South Korea.
Stem Cells Transl Med. 2025 May 31;14(6). doi: 10.1093/stcltm/szaf019.
Ample evidence suggests that α-synuclein (αSyn) accumulation in the endoplasmic reticulum (ER) leads to ER stress, resulting in neurodegeneration in Parkinson's disease (PD). Selective degradation of accumulated αSyn 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 αSyn specifically in the ER (ER-αSyn), co-culture with MSCs promoted ER-αSyn clearance through selective ER-phagy and also recovered cell viability. Injection of MSCs to an animal model using adeno-associated virus vectors to overexpress αSyn in the ER (AAV-ER- αSyn), 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 αSyn in PD cellular and murine models.
大量证据表明，内质网（ER）中α-突触核蛋白（αSyn）的积累会导致内质网应激，进而引发帕金森病（PD）中的神经退行性变。通过内质网自噬选择性降解积累的αSyn可以减轻内质网应激并挽救神经退行性变。在本研究中，我们调查了间充质干细胞（MSCs）是否通过调节内质网自噬对PD发挥神经保护作用。在一个在内质网中特异性过表达αSyn的细胞模型（内质网-αSyn）中，与MSCs共培养通过选择性内质网自噬促进了内质网-αSyn的清除，还恢复了细胞活力。使用腺相关病毒载体将MSCs注射到一个在内质网中过表达αSyn的动物模型（AAV-ER-αSyn）中，也降低了内质网中αSyn的表达，减轻了黑质（SN）中多巴胺能神经元的损失和纹状体（ST）中的去神经支配，随后运动功能障碍得到改善。体外筛选确定MSCs通过调节核亚家族4 A组成员1（NR4A1）转录因子促进了序列相似性家族134成员B（FAM134B）介导的内质网自噬，并在体内得到了验证。本研究表明，MSCs在NR4A1的调节下调节FAM134B介导的内质网自噬，促进PD细胞和小鼠模型中内质网积累的αSyn的清除。
