PMID- 12397073
OWN - NLM
STAT- MEDLINE
DCOM- 20030227
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 277
IP  - 52
DP  - 2002 Dec 27
TI  - Alpha-synuclein lowers p53-dependent apoptotic response of neuronal cells. 
      Abolishment by 6-hydroxydopamine and implication for Parkinson's disease.
PG  - 50980-4
AB  - We have examined the influence of alpha-synuclein on the responsiveness of TSM1 
      neuronal cells to apoptotic stimulus. We show that alpha-synuclein drastically 
      lowers basal and staurosporine-stimulated caspase 3 immunoreactivity and 
      activity. This is accompanied by lower DNA fragmentation and reduced number of 
      terminal deoxynucleotide transferase-mediated dUTP nick end labeling 
      (TUNEL)-positive neurons. Interestingly, alpha-synuclein also diminishes both p53 
      expression and transcriptional activity. We demonstrate that the antiapoptotic 
      phenotype displayed by alpha-synuclein can be fully reversed by the Parkinson's 
      disease-associated dopamine derivative 6-hydroxydopamine. Thus, 6-hydroxydopamine 
      fully abolishes the alpha-synuclein-mediated reduction of caspase 3 activity and 
      reverses the associated decrease of p53 expression. 6-Hydroxydopamine triggers 
      thioflavin T-positive deposits in alpha-synuclein, but not mock-transfected TSM1 
      neurons, and drastically increases alpha-synuclein immunoreactivity. Altogether, 
      we suggest that alpha-synuclein lowers the p53-dependent caspase 3 activation of 
      TSM1 in response to apoptotic stimuli and we propose that the natural toxin 
      6-hydroxydopamine abolishes this antiapoptotic phenotype by triggering 
      alpha-synuclein aggregation, thereby likely contributing to Parkinson's disease 
      neuropathology.
FAU - Alves Da Costa, Cristine
AU  - Alves Da Costa C
AD  - Institut de Pharmacologie Moleculaire et Cellulaire du CNRS, UMR6097, 660 route 
      des Lucioles, 06560 Valbonne, France.
FAU - Paitel, Erwan
AU  - Paitel E
FAU - Vincent, Bruno
AU  - Vincent B
FAU - Checler, Frederic
AU  - Checler F
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20021022
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Recombinant Proteins)
RN  - 0 (SNCA protein, human)
RN  - 0 (Synucleins)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 0 (alpha-Synuclein)
RN  - 8HW4YBZ748 (Oxidopamine)
RN  - EC 3.4.22.- (CASP3 protein, human)
RN  - EC 3.4.22.- (Caspase 3)
RN  - EC 3.4.22.- (Caspases)
SB  - IM
MH  - Apoptosis/drug effects/*physiology
MH  - Caspase 3
MH  - Caspases/metabolism
MH  - Cell Line
MH  - Cells, Cultured
MH  - Humans
MH  - Kidney
MH  - Kinetics
MH  - Models, Biological
MH  - Nerve Tissue Proteins/genetics/*physiology
MH  - Neurons/*cytology/drug effects/physiology
MH  - Oxidopamine/*pharmacology
MH  - Parkinson Disease/*pathology/physiopathology
MH  - Recombinant Proteins/metabolism
MH  - Synucleins
MH  - Transfection
MH  - Tumor Suppressor Protein p53/*physiology
MH  - alpha-Synuclein
EDAT- 2002/10/25 04:00
MHDA- 2003/02/28 04:00
CRDT- 2002/10/25 04:00
PHST- 2002/10/25 04:00 [pubmed]
PHST- 2003/02/28 04:00 [medline]
PHST- 2002/10/25 04:00 [entrez]
AID - S0021-9258(19)31423-1 [pii]
AID - 10.1074/jbc.M207825200 [doi]
PST - ppublish
SO  - J Biol Chem. 2002 Dec 27;277(52):50980-4. doi: 10.1074/jbc.M207825200. Epub 2002 
      Oct 22.