PMID- 21330369
OWN - NLM
STAT- MEDLINE
DCOM- 20110628
LR  - 20211020
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 286
IP  - 16
DP  - 2011 Apr 22
TI  - Role of matrix metalloproteinase 3-mediated alpha-synuclein cleavage in 
      dopaminergic cell death.
PG  - 14168-77
LID - 10.1074/jbc.M111.222430 [doi]
AB  - Evidence suggests that the C-terminal truncation of alpha-synuclein is equally 
      important as aggregation of alpha-synuclein in Parkinson disease (PD). Our previous 
      results showed that an endopeptidase, matrix metalloproteinase-3 (MMP3), was 
      induced and activated in dopaminergic (DA) cells upon stress conditions. Here, we 
      report that MMP3 cleaved alpha-synuclein in vitro and in vivo and that alpha-synuclein 
      and MMP3 were co-localized in Lewy bodies (LB) in the postmortem brains of PD 
      patients. Incubation of alpha-synuclein with the catalytic domain of MMP3 (cMMP3) 
      resulted in generation of several peptides, and the peptide profiles of WT 
      alpha-synuclein (WTsyn) and A53T mutant (A53Tsyn) were different. Combined analysis 
      using mass spectrometry and N-terminal determination revealed that MMP3 generated 
      C-terminally truncated peptides of amino acids 1-78, 1-91, and 1-93 and that 
      A53Tsyn produced significantly higher quantities of these peptides. Similar sizes 
      of peptides were detected in N27 DA cells under oxidative stress and RNA 
      interference to knock down MMP3-attenuated peptide generation. Co-overexpression 
      of cMMP3 with either WTsyn or A53Tsyn led to a reduction in Triton 
      X-100-insoluble aggregates and an increase in protofibril-like small aggregates. 
      In addition, overexpression of the 1-93-amino acid peptide in the substantia 
      nigra led to DA neuronal loss without LB-like aggregate formation. The results 
      strongly indicate that MMP3 digestion of alpha-synuclein in DA neurons plays a 
      pivotal role in the progression of PD through modulation of alpha-synuclein in 
      aggregation, LB formation, and neurotoxicity.
FAU - Choi, Dong-Hee
AU  - Choi DH
AD  - Neurology/Neuroscience Department, Weill Medical College of Cornell University, 
      New York, New York 10065, USA.
FAU - Kim, Youn-Jung
AU  - Kim YJ
FAU - Kim, Young-Gun
AU  - Kim YG
FAU - Joh, Tong H
AU  - Joh TH
FAU - Beal, M Flint
AU  - Beal MF
FAU - Kim, Yoon-Seong
AU  - Kim YS
LA  - eng
GR  - R01 NS062827/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110217
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Recombinant Proteins)
RN  - 0 (alpha-Synuclein)
RN  - EC 3.4.24.17 (Matrix Metalloproteinase 3)
RN  - VTD58H1Z2X (Dopamine)
SB  - IM
MH  - Animals
MH  - Catalytic Domain
MH  - Cell Death
MH  - Dopamine/*metabolism
MH  - Female
MH  - *Gene Expression Regulation, Enzymologic
MH  - Humans
MH  - Lewy Bodies/*metabolism
MH  - Matrix Metalloproteinase 3/*metabolism
MH  - Parkinson Disease/*metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Recombinant Proteins/chemistry
MH  - Substantia Nigra/metabolism
MH  - alpha-Synuclein/*metabolism
PMC - PMC3077618
EDAT- 2011/02/19 06:00
MHDA- 2011/06/29 06:00
PMCR- 2012/04/22
CRDT- 2011/02/19 06:00
PHST- 2011/02/19 06:00 [entrez]
PHST- 2011/02/19 06:00 [pubmed]
PHST- 2011/06/29 06:00 [medline]
PHST- 2012/04/22 00:00 [pmc-release]
AID - S0021-9258(20)51511-1 [pii]
AID - M111.222430 [pii]
AID - 10.1074/jbc.M111.222430 [doi]
PST - ppublish
SO  - J Biol Chem. 2011 Apr 22;286(16):14168-77. doi: 10.1074/jbc.M111.222430. Epub 
      2011 Feb 17.