PMID- 32350025
OWN - NLM
STAT- MEDLINE
DCOM- 20201228
LR  - 20211103
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 295
IP  - 23
DP  - 2020 Jun 5
TI  - The GTPase Rab27b regulates the release, autophagic clearance, and toxicity of 
      alpha-synuclein.
PG  - 8005-8016
LID - 10.1074/jbc.RA120.013337 [doi]
AB  - alpha-Synuclein (alphasyn) is the primary component of proteinaceous aggregates termed 
      Lewy bodies that pathologically define synucleinopathies including Parkinson's 
      disease (PD) and dementia with Lewy bodies (DLB). alphasyn is hypothesized to spread 
      through the brain in a prion-like fashion by misfolded protein forming a template 
      for aggregation of endogenous alphasyn. The cell-to-cell release and uptake of alphasyn 
      are considered important processes for its prion-like spread. Rab27b is one of 
      several GTPases essential to the endosomal-lysosomal pathway and is implicated in 
      protein secretion and clearance, but its role in alphasyn spread has yet to be 
      characterized. In this study, we used a paracrine alphasyn in vitro neuronal model to 
      test the impact of Rab27b on alphasyn release, clearance, and toxicity. 
      shRNA-mediated knockdown (KD) of Rab27b increased alphasyn-mediated paracrine 
      toxicity. Rab27b reduced alphasyn release primarily through nonexosomal pathways, but 
      the alphasyn released after Rab27b KD was of higher-molecular-weight species, as 
      determined by size-exclusion chromatography. Rab27b KD increased intracellular 
      levels of insoluble alphasyn and led to an accumulation of endogenous light chain 3 
      (LC3)-positive puncta. Rab27b KD also decreased LC3 turnover after treatment with 
      an autophagosome-lysosome fusion inhibitor, chloroquine, indicating that Rab27b 
      KD induces a defect in autophagic flux. Rab27b protein levels were increased in 
      brain lysates obtained from postmortem tissues of individuals with PD and DLB 
      compared with healthy controls. These data indicate a role for Rab27b in the 
      release, clearance, and toxicity of alphasyn and, ultimately, in the pathogenesis of 
      synucleinopathies.
CI  - (c) 2020 Underwood et al.
FAU - Underwood, Rachel
AU  - Underwood R
AUID- ORCID: 0000-0003-3630-7007
AD  - Center for Neurodegeneration and Experimental Therapeutics, Department of 
      Neurology, University of Alabama at Birmingham, Birmingham, Alabama.
FAU - Wang, Bing
AU  - Wang B
AD  - Center for Neurodegeneration and Experimental Therapeutics, Department of 
      Neurology, University of Alabama at Birmingham, Birmingham, Alabama.
FAU - Carico, Christine
AU  - Carico C
AUID- ORCID: 0000-0001-7426-8200
AD  - Department of Biochemistry and Molecular Genetics, University of Alabama at 
      Birmingham, Birmingham, Alabama.
FAU - Whitaker, Robert H
AU  - Whitaker RH
AUID- ORCID: 0000-0002-9751-0423
AD  - Department of Biochemistry and Molecular Genetics, University of Alabama at 
      Birmingham, Birmingham, Alabama.
FAU - Placzek, William J
AU  - Placzek WJ
AUID- ORCID: 0000-0003-4096-8617
AD  - Department of Biochemistry and Molecular Genetics, University of Alabama at 
      Birmingham, Birmingham, Alabama.
FAU - Yacoubian, Talene A
AU  - Yacoubian TA
AUID- ORCID: 0000-0003-2227-7310
AD  - Center for Neurodegeneration and Experimental Therapeutics, Department of 
      Neurology, University of Alabama at Birmingham, Birmingham, Alabama 
      tyacoubian@uabmc.edu.
LA  - eng
GR  - P50 NS108675/NS/NINDS NIH HHS/United States
GR  - R01 NS112203/NS/NINDS NIH HHS/United States
GR  - R01 NS088533/NS/NINDS NIH HHS/United States
GR  - R01 GM117391/GM/NIGMS NIH HHS/United States
GR  - P30 AG019610/AG/NIA NIH HHS/United States
GR  - T32 GM008361/GM/NIGMS NIH HHS/United States
GR  - F31 NS106733/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200429
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (RNA, Small Interfering)
RN  - 0 (alpha-Synuclein)
RN  - EC 3.6.1.-. (Rab27B protein, human)
RN  - EC 3.6.5.2 (rab GTP-Binding Proteins)
SB  - IM
MH  - *Autophagy/drug effects
MH  - Cell Line, Tumor
MH  - Humans
MH  - Paracrine Communication/drug effects
MH  - RNA, Small Interfering/pharmacology
MH  - alpha-Synuclein/antagonists & inhibitors/*metabolism
MH  - rab GTP-Binding Proteins/antagonists & inhibitors/*metabolism
PMC - PMC7278354
OTO - NOTNLM
OT  - Lewy body
OT  - Parkinson's disease
OT  - RAS oncogene family
OT  - Rab
OT  - autophagy
OT  - dementia with Lewy bodies
OT  - exosome (vesicle)
OT  - neurodegeneration
OT  - protein misfolding
OT  - synucleinopathy
OT  - alpha-synuclein
COIS- Conflict of interest-The authors declare that they have no conflicts of interest 
      with the contents of this article.
EDAT- 2020/05/01 06:00
MHDA- 2020/12/29 06:00
PMCR- 2021/06/05
CRDT- 2020/05/01 06:00
PHST- 2020/03/09 00:00 [received]
PHST- 2020/04/24 00:00 [revised]
PHST- 2020/05/01 06:00 [pubmed]
PHST- 2020/12/29 06:00 [medline]
PHST- 2020/05/01 06:00 [entrez]
PHST- 2021/06/05 00:00 [pmc-release]
AID - S0021-9258(17)49439-7 [pii]
AID - RA120.013337 [pii]
AID - 10.1074/jbc.RA120.013337 [doi]
PST - ppublish
SO  - J Biol Chem. 2020 Jun 5;295(23):8005-8016. doi: 10.1074/jbc.RA120.013337. Epub 
      2020 Apr 29.