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

Proc Natl Acad Sci U S A. 2023 Sep 12;120(37):e2221929120. doi: 10.1073/pnas.2221929120. Epub 2023 Sep 5.


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.

Keywords: ER-phagy; FAM134B; Parkinson’s disease; protection; α-synuclein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagy
  • Endoplasmic Reticulum
  • Humans
  • Neuroprotective Agents*
  • Parkinson Disease*
  • alpha-Synuclein


  • alpha-Synuclein
  • Neuroprotective Agents