PMID- 22921536
OWN - NLM
STAT- MEDLINE
DCOM- 20130121
LR  - 20211021
IS  - 1090-2430 (Electronic)
IS  - 0014-4886 (Print)
IS  - 0014-4886 (Linking)
VI  - 238
IP  - 2
DP  - 2012 Dec
TI  - Ubiquitin proteasome system in Parkinson's disease: a keeper or a witness?
PG  - 89-99
LID - S0014-4886(12)00317-2 [pii]
LID - 10.1016/j.expneurol.2012.08.008 [doi]
AB  - OBJECTIVE: The aim of this work was to evaluate the role of ubiquitin-proteasome 
      system (UPS) on mitochondrial-driven alpha-synuclein (aSN) clearance in in vitro, 
      ex vivo and in vivo Parkinson's disease (PD) cellular models. METHOD: We used 
      SH-SY5Y ndufa2 knock-down (KD) cells, PD cybrids and peripheral blood mononuclear 
      cells (PBMC) from patients meeting the diagnostic criteria for PD. We quantified 
      aSN aggregation, proteasome activity and protein ubiquitination levels. In PBMC 
      of PD patient population we evaluated the aSN levels in the plasma and the 
      influence of several demographic characteristics in the above mentioned 
      determinations. RESULTS: We found that ubiquitin-independent proteasome activity 
      was up-regulated in SH-SY5Y ndufa2 KD cells while a downregulation was observed 
      in PD cybrids and PBMC. Moreover, we observed an increase in protein 
      ubiquitination that correlates with a decrease in ubiquitin-dependent proteasome 
      activity. Accordingly, proteasome inhibition prevented ubiquitin-dependent aSN 
      clearance. Ubiquitin-independent proteasome activity was positively correlated 
      with ubiquitination in PBMC. We also report a negative correlation of 
      chymotrypsin-like activity with age in control and late-onset PD groups. Total 
      ubiquitin content is positively correlated with aSN oligomer levels, which leads 
      to an age-dependent increase of aSN ubiquitination in LOPD. Moreover, aSN levels 
      are increased in the plasma of PD patients. INTERPRETATION: aSN oligomers are 
      ubiquitinated and we identified a ubiquitin-dependent clearance insufficiency 
      with the accumulation of both aSN and ubiquitin. However, SH-SY5Y ndufa2 KD cells 
      showed a significant up-regulation of ubiquitin-independent proteasomal enzymatic 
      activity that could mean a cell rescue attempt. Moreover, we identified that UPS 
      function is age-dependent in PBMC.
CI  - Copyright (c) 2012 Elsevier Inc. All rights reserved.
FAU - Martins-Branco, Diogo
AU  - Martins-Branco D
AD  - CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Portugal.
FAU - Esteves, Ana R
AU  - Esteves AR
FAU - Santos, Daniel
AU  - Santos D
FAU - Arduino, Daniela M
AU  - Arduino DM
FAU - Swerdlow, Russell H
AU  - Swerdlow RH
FAU - Oliveira, Catarina R
AU  - Oliveira CR
FAU - Januario, Cristina
AU  - Januario C
FAU - Cardoso, Sandra M
AU  - Cardoso SM
LA  - eng
GR  - P30 AG035982/AG/NIA NIH HHS/United States
GR  - P30AG035982/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120819
PL  - United States
TA  - Exp Neurol
JT  - Experimental neurology
JID - 0370712
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Tetrazolium Salts)
RN  - 0 (Thiazoles)
RN  - 0 (Ubiquitin)
RN  - 147336-22-9 (Green Fluorescent Proteins)
RN  - 33X04XA5AT (Lactic Acid)
RN  - EC 2.3.3.1 (Citrate (si)-Synthase)
RN  - EC 3.4.21.1 (Chymotrypsin)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
RN  - EC 7.1.1.2 (Electron Transport Complex I)
RN  - EUY85H477I (thiazolyl blue)
SB  - IM
CIN - Exp Neurol. 2013 Sep;247:308-13. PMID: 23499831
MH  - Adult
MH  - Age Factors
MH  - Aged
MH  - Aged, 80 and over
MH  - Analysis of Variance
MH  - Case-Control Studies
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - Chymotrypsin/metabolism
MH  - Citrate (si)-Synthase/metabolism
MH  - Electron Transport Complex I
MH  - Female
MH  - Green Fluorescent Proteins/genetics
MH  - Humans
MH  - Immunoprecipitation
MH  - Lactic Acid/pharmacology
MH  - Leukocytes, Mononuclear/metabolism
MH  - Male
MH  - Middle Aged
MH  - Mitochondria/genetics/metabolism
MH  - Neuroblastoma/pathology
MH  - Parkinson Disease/blood/genetics/*metabolism/pathology
MH  - Plasma/metabolism
MH  - Proteasome Endopeptidase Complex/genetics/*metabolism
MH  - RNA, Small Interfering/genetics/metabolism
MH  - Statistics as Topic
MH  - Tetrazolium Salts
MH  - Thiazoles
MH  - Transfection
MH  - Ubiquitin/genetics/*metabolism
MH  - Ubiquitination/drug effects/genetics
MH  - Up-Regulation/drug effects/genetics
PMC - PMC4077023
MID - NIHMS602935
EDAT- 2012/08/28 06:00
MHDA- 2013/01/23 06:00
PMCR- 2014/07/01
CRDT- 2012/08/28 06:00
PHST- 2012/07/06 00:00 [received]
PHST- 2012/07/26 00:00 [revised]
PHST- 2012/08/07 00:00 [accepted]
PHST- 2012/08/28 06:00 [entrez]
PHST- 2012/08/28 06:00 [pubmed]
PHST- 2013/01/23 06:00 [medline]
PHST- 2014/07/01 00:00 [pmc-release]
AID - S0014-4886(12)00317-2 [pii]
AID - 10.1016/j.expneurol.2012.08.008 [doi]
PST - ppublish
SO  - Exp Neurol. 2012 Dec;238(2):89-99. doi: 10.1016/j.expneurol.2012.08.008. Epub 
      2012 Aug 19.