A selective ER-phagy exerts neuroprotective effects via modulation of α-synuclein clearance in parkinsonian models
Dong Yeol Kim, Jin Young Shin, Ji Eun Lee, Hana Kim, Seok Jong Chung, Han Soo Yoo, Sang Jin Kim, Hwa Jin Cho, Eun‐Jae Lee, Soo Jeong Nam, Seong Heon Kim, Jae‐Won Jang, Seung Eun Lee, Phil Hyu Lee
Abstract
The endoplasmic reticulum (ER) is selectively degraded by ER-phagy to maintain cell homeostasis. α-synuclein accumulates in the ER, causing ER stress that contributes to neurodegeneration in Parkinson's disease (PD), but the role of ER-phagy in α-synuclein modulation is largely unknown. Here, we investigated the mechanisms by which ER-phagy selectively recognizes α-synuclein for degradation in the ER. We found that ER-phagy played an important role in the degradation of α-synuclein and recovery of ER function through interaction with FAM134B, where calnexin is required for the selective FAM134B-mediated α-synuclein clearance via ER-phagy. Overexpression of α-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 α-synuclein.