A selective ER-phagy exerts neuroprotective effects via modulation of α-synuclein clearance in parkinsonian models

Abstract

The endoplasmic reticulum (ER) is selectively degraded by ER-phagy to maintain cell homeostasis. alpha-synuclein accumulates in the ER, causing ER stress that contributes to neurodegeneration in Parkinson's disease (PD), but the role of ER-phagy in alpha-synuclein modulation is largely unknown. Here, we investigated the mechanisms by which ER-phagy selectively recognizes alpha-synuclein for degradation in the ER. We found that ER-phagy played an important role in the degradation of alpha-synuclein and recovery of ER function through interaction with FAM134B, where calnexin is required for the selective FAM134B-mediated alpha-synuclein clearance via ER-phagy. Overexpression of alpha-synuclein in the ER of the substantia nigra (SN) resulted in marked loss of dopaminergic neurons and motor deficits, mimicking PD characteristics. However, enhancement of ER-phagy using FAM134B overexpression in the SN exerted neuroprotective effects on dopaminergic neurons and recovered motor performance. These data suggest that ER-phagy represents a specific ER clearance mechanism for the degradation of alpha-synuclein.