PMID- 34662812
OWN - NLM
STAT- MEDLINE
DCOM- 20211130
LR  - 20220531
IS  - 2213-2317 (Electronic)
IS  - 2213-2317 (Linking)
VI  - 47
DP  - 2021 Nov
TI  - Deficient immunoproteasome assembly drives gain of alpha-synuclein pathology in 
      Parkinson's disease.
PG  - 102167
LID - S2213-2317(21)00327-X [pii]
LID - 10.1016/j.redox.2021.102167 [doi]
LID - 102167
AB  - Aberrant alpha-synuclein (alpha-Syn) accumulation resulting from proteasome dysfunction 
      is considered as a prominent factor to initiate and aggravate the 
      neurodegeneration in Parkinson's disease (PD). Although the involvement of 26S 
      proteasome in proteostasis imbalance has been widely accepted, our knowledge 
      about the regulation of immunoproteasome function and its potential role in alpha-Syn 
      pathology remains limited. Immunoproteasome abundance and proteolytic activities 
      depend on the finely tuned assembly process, especially beta-ring formation mediated 
      by the only well-known chaperone proteasome maturation protein (POMP). Here, we 
      identified that alpha-Syn overexpression was associated with a reduction in 
      immunoproteasome function, which in turn limited the degradation of polo-like 
      kinase 2 (PLK2), exacerbated alpha-Syn Ser129 phosphorylation and aggregation, 
      ultimately leading to the neurodegeneration. These effects could be dramatically 
      attenuated by beta5i overexpression. Mechanistically, alpha-Syn suppressed the 
      transcriptional regulation of POMP by nuclear factor erythroid 2-related factor 2 
      (NRF2), thereby preventing the assembly of immunoproteasome beta subunits. 
      Dopaminergic neurons-specific overexpression of NRF2-POMP axis effectively 
      rescued the aggregation of alpha-Syn and PD-like phenotypes. These findings 
      characterized abnormal immunoproteasome assembly as a key contributor governing 
      alpha-Syn accumulation and neurodegeneration, which might open up a new perspective 
      for the implication of immunoproteasome in PD and provide approaches of 
      manipulating immunoproteasome assembly for therapeutic purposes.
CI  - Copyright (c) 2021 The Authors. Published by Elsevier B.V. All rights reserved.
FAU - Bi, Mingxia
AU  - Bi M
AD  - Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and 
      Prevention of Neurological Disorders and State Key Disciplines: Physiology, 
      School of Basic Medicine, Medical College, Qingdao University, Qingdao, China.
FAU - Du, Xixun
AU  - Du X
AD  - Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and 
      Prevention of Neurological Disorders and State Key Disciplines: Physiology, 
      School of Basic Medicine, Medical College, Qingdao University, Qingdao, China.
FAU - Xiao, Xue
AU  - Xiao X
AD  - Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and 
      Prevention of Neurological Disorders and State Key Disciplines: Physiology, 
      School of Basic Medicine, Medical College, Qingdao University, Qingdao, China.
FAU - Dai, Yingying
AU  - Dai Y
AD  - Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and 
      Prevention of Neurological Disorders and State Key Disciplines: Physiology, 
      School of Basic Medicine, Medical College, Qingdao University, Qingdao, China.
FAU - Jiao, Qian
AU  - Jiao Q
AD  - Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and 
      Prevention of Neurological Disorders and State Key Disciplines: Physiology, 
      School of Basic Medicine, Medical College, Qingdao University, Qingdao, China.
FAU - Chen, Xi
AU  - Chen X
AD  - Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and 
      Prevention of Neurological Disorders and State Key Disciplines: Physiology, 
      School of Basic Medicine, Medical College, Qingdao University, Qingdao, China.
FAU - Zhang, Lingqiang
AU  - Zhang L
AD  - State Key Laboratory of Proteomics, National Center for Protein Sciences 
      (Beijing), Beijing Institute of Lifeomics, Beijing, China.
FAU - Jiang, Hong
AU  - Jiang H
AD  - Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and 
      Prevention of Neurological Disorders and State Key Disciplines: Physiology, 
      School of Basic Medicine, Medical College, Qingdao University, Qingdao, China. 
      Electronic address: hongjiang@qdu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20211014
PL  - Netherlands
TA  - Redox Biol
JT  - Redox biology
JID - 101605639
RN  - 0 (alpha-Synuclein)
SB  - IM
MH  - Animals
MH  - Disease Models, Animal
MH  - Dopaminergic Neurons/metabolism
MH  - Humans
MH  - Mice
MH  - Mice, Transgenic
MH  - *Parkinson Disease/genetics
MH  - Phosphorylation
MH  - Proteostasis
MH  - *alpha-Synuclein/genetics/metabolism
PMC - PMC8577461
OTO - NOTNLM
OT  - Immunoproteasome
OT  - NRF2
OT  - POMP
OT  - Parkinson's disease
OT  - alpha-synuclein
COIS- The authors declare that they have no known competing financial interests or 
      personal relationships that could have appeared to influence the work reported in 
      this paper.
EDAT- 2021/10/19 06:00
MHDA- 2021/12/01 06:00
PMCR- 2021/10/14
CRDT- 2021/10/18 20:18
PHST- 2021/09/05 00:00 [received]
PHST- 2021/10/11 00:00 [revised]
PHST- 2021/10/13 00:00 [accepted]
PHST- 2021/10/19 06:00 [pubmed]
PHST- 2021/12/01 06:00 [medline]
PHST- 2021/10/18 20:18 [entrez]
PHST- 2021/10/14 00:00 [pmc-release]
AID - S2213-2317(21)00327-X [pii]
AID - 102167 [pii]
AID - 10.1016/j.redox.2021.102167 [doi]
PST - ppublish
SO  - Redox Biol. 2021 Nov;47:102167. doi: 10.1016/j.redox.2021.102167. Epub 2021 Oct 
      14.