Mitochondrial associated metabolic proteins are selectively oxidized in A30P α-synuclein transgenic mice - A model of familial Parkinson's disease

H. Fai Poon, Mark Frasier, Nathan Shreve, Vittorio Calabrese, Benjamin Wolozin, D. Allan Butterfield

Research output: Contribution to journalArticlepeer-review

148 Scopus citations

Abstract

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. α-Synuclein is strongly implicated in the pathophysiology of PD because aggregated α-synuclein accumulates in the brains of subjects with PD, mutations in α-synuclein cause familial PD, and overexpressing mutant human α-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 α-synuclein contribute to the pathophysiology of PD, we undertook a proteomic analysis of transgenic mice overexpressing A30P α-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 α-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 α-synuclein.

Original languageEnglish
Pages (from-to)492-498
Number of pages7
JournalNeurobiology of Disease
Volume18
Issue number3
DOIs
StatePublished - Apr 2005

Bibliographical note

Funding Information:
The authors would like to thank Susan Debusca and Marcia Butterfield for assistance in the preparation of the manuscript. This work was supported in part by grants from NIH [AG-105119; AG-10836] to D.A.B. and from NIH [NS41786] and DAMD [17-01-1-0781] to B.W.

Keywords

  • A30P
  • Alpha-synuclein
  • Carbonic anhydrase
  • Enolase
  • Lactate dehydrogenase
  • Oxidative stress
  • Parkinson's disease
  • Protein oxidation

ASJC Scopus subject areas

  • Neurology

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