Mitochondrial associated metabolic proteins are selectively oxidized in A30P alpha-synuclein transgenic mice--a model of familial Parkinson's disease.
Parkinson's disease (PD) is the most common neurodegenerative movement disorder and is characterized by the loss of dopaminergic neurons in the substantia nigra compacta. alpha-Synuclein is strongly implicated in the pathophysiology of PD because aggregated alpha-synuclein accumulates in the brains of subjects with PD, mutations in alpha-synuclein cause familial PD, and overexpressing mutant human alpha-synuclein (A30P or A53T) causes degenerative disease in mice or drosophila. The pathophysiology of PD is poorly understood, but increasing evidence implicates mitochondrial dysfunction and oxidative stress. To understand how mutations in alpha-synuclein contribute to the pathophysiology of PD, we undertook a proteomic analysis of transgenic mice overexpressing A30P alpha-synuclein to investigate which proteins are oxidized. We observed more than twofold selective increases in specific carbonyl levels of three metabolic proteins in brains of symptomatic A30P alpha-synuclein mice: carbonic anhydrase 2 (Car2), alpha-enolase (Eno1), and lactate dehydrogenase 2 (Ldh2). Analysis of the activities of these proteins demonstrates decreased functions of these oxidatively modified proteins in brains from the A30P compared to control mice. Our findings suggest that proteins associated with impaired energy metabolism and mitochondria are particularly prone to oxidative stress associated with A30P-mutant alpha-synuclein.
Poon
H Fai
HF
Department of Chemistry, University of Kentucky, Lexington, KY 40506-0055, USA.
Frasier
Mark
M
Shreve
Nathan
N
Calabrese
Vittorio
V
Wolozin
Benjamin
B
Butterfield
D Allan
DA
D000409:Alanine / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D011392:Proline / Q000235:genetics*; D051843:Synucleins; D051844:alpha-Synuclein
D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; C497605:Snca protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein; D011392:Proline; D000409:Alanine