Alpha-synuclein protects naive but not dbcAMP-treated dopaminergic cell types from 1-methyl-4-phenylpyridinium toxicity.
The pre-synaptic protein, alpha-synuclein, has been associated with the pathogenesis of Parkinson's disease. The present study indicates that alpha-synuclein, but not its mutants (A53T, A30P), can protect CNS dopaminergic cells from the parkinsonism-inducing drug 1-methyl-4-phenylpyridinium (MPP+), whereas it cannot protect from the dopaminergic toxin, 6-hydroxydopamine, hydrogen-peroxide, or the beta-amyloid peptide, A-beta. Protection from MPP+ was directly correlated with the preservation of mitochondrial function. Specifically, alpha-synuclein rescued cells from MPP+ mediated decreases in mitochondrial dehydrogenase activity and loss of ATP levels by utilizing ketosis. It also prevented toxin-induced activation of the creatine kinase/creatine phosphate system. Similarly, alpha-synuclein protected cells from the complex I inhibitor rotenone and 3-nitroproprionic acid, a complex II inhibitor. Wild-type alpha-synuclein-mediated neuroprotection and subsequent alterations in energy were not found in dbcAMP-differentiated cells. These results suggest that the normal physiological role for alpha-synuclein may change during development.
Jensen
Penny J
PJ
Washington University School of Medicine, Anatomy and Neurobiology Department, St Louis, Missouri 63110, USA.
Alter
Benedict J
BJ
O'Malley
Karen L
KL
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D004579:Electron Transport / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D007657:Ketone Bodies / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000633:toxicity; D016877:Oxidants / Q000633:toxicity; D016627:Oxidopamine / Q000633:toxicity; D010446:Peptide Fragments / Q000633:toxicity; D051843:Synucleins; D014162:Transfection; D051844:alpha-Synuclein
D016229:Amyloid beta-Peptides; D007657:Ketone Bodies; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009498:Neurotoxins; D016877:Oxidants; D010446:Peptide Fragments; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein; C078592:amyloid beta-protein (1-40); C074636:amyloid beta-protein (25-35); D003994:Bucladesine; D016627:Oxidopamine; D006861:Hydrogen Peroxide; D015655:1-Methyl-4-phenylpyridinium