Alpha-synuclein facilitates the toxicity of oxidized catechol metabolites: implications for selective neurodegeneration in Parkinson's disease.
Free radicals, including dopamine (DA)-oxidized metabolites, have long been implicated in pathogenesis of Parkinson's disease (PD). However, the relationships between such oxidative stresses and alpha-synuclein (alpha-S), a major constituent of Lewy bodies, remain unknown. In this study, we established neuronal cells that constitutively express alpha-S and tetracycline-regulated tyrosinase. While tyrosinase overexpression induced apoptosis, co-expression of wild type or A53T mutant human alpha-S with tyrosinase further exacerbated cell death. In this process, the formation of alpha-S oligomers and the reduction in mitochondrial membrane potential were demonstrated. This cellular model may reconstitute the pathological metabolism of alpha-S in the synucleinopathy and provide a useful tool to explore possible pathomechanisms of nigral degeneration in PD.
Hasegawa
Takafumi
T
Department of Neurology, Tohoku University School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai, Miyagi 980-8574, Japan.
Matsuzaki-Kobayashi
Michiko
M
Takeda
Atsushi
A
Sugeno
Naoto
N
Kikuchi
Akio
A
Furukawa
Katsutoshi
K
Perry
George
G
Smith
Mark A
MA
Itoyama
Yasuto
Y
D017209:Apoptosis; D002396:Catechols / Q000378:metabolism* / Q000633:toxicity*; D002478:Cells, Cultured; D020552:Comet Assay; D004249:DNA Damage; D004789:Enzyme Activation; D015870:Gene Expression; D006801:Humans; D007425:Intracellular Membranes; D008564:Membrane Potentials; D051336:Mitochondrial Membranes / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008970:Molecular Weight; D014442:Monophenol Monooxygenase / Q000378:metabolism; D046912:Multiprotein Complexes; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000473:pathology*; D010084:Oxidation-Reduction; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology*; D051844:alpha-Synuclein / Q000378:metabolism*
D002396:Catechols; D046912:Multiprotein Complexes; D051844:alpha-Synuclein; D014442:Monophenol Monooxygenase; D020928:Mitogen-Activated Protein Kinases; C034221:catechol