Mesenchymal stem cells enhance selective ER-phagy to promote α-synuclein clearance in Parkinson’s disease

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.