The ER retention protein RER1 promotes alpha-synuclein degradation via the proteasome.

ABSTRACT: Abnormal accumulation of ?-synuclein (?Syn) has been linked to endoplasmic-reticulum (ER) stress, defective intracellular protein/vesicle trafficking, and cytotoxicity. Targeting factors involved in ER-related protein processing and trafficking may, therefore, be a key to modulating ?Syn levels and associated toxicity. Recently retention in endoplasmic reticulum 1 (RER1) has been identified as an important ER retrieval/retention factor for Alzheimer's disease proteins and negatively regulates amyloid-? peptide levels. Here, we hypothesized that RER1 might also play an important role in retention/retrieval of ?Syn and mediate levels. We expressed RER1 and a C-terminal mutant RER1?25, which lacks the ER retention/retrieval function, in HEK293 and H4 neuroglioma cells. RER1 overexpression significantly decreased levels of both wild type and A30P, A53T, and E46K disease causal mutants of ?Syn, whereas the RER1?25 mutant had a significantly attenuated effect on ?Syn. RER1 effects were specific to ?Syn and had little to no effect on either ?Syn or the ?71-82 ?Syn mutant, which both lack the NAC domain sequence critical for synuclein fibrillization. Tests with proteasomal and macroautophagy inhibitors further demonstrate that RER1 effects on ?Syn are primarily mediated through the ubiquitin-proteasome system. RER1 also appears to interact with the ubiquitin ligase NEDD4. RER1 in human diseased brain tissues co-localizes with ?Syn-positive Lewy bodies. Together, these findings provide evidence that RER1 is a novel and potential important mediator of elevated ?Syn levels. Further investigation of the mechanism of RER1 and downstream effectors on ?Syn may yield novel therapeutic targets for modulation in Parkinson disease and related synucleinopathies.

SUBMITTER: Park HJ 

PROVIDER: S-EPMC5587320 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature