α‐Synuclein protects naive but not dbcAMP‐treated dopaminergic cell types from 1‐methyl‐4‐phenylpyridinium toxicity

Abstract

The pre-synaptic protein, a-synuclein, has been associated with the pathogenesis of Parkinson's disease. The present study indicates that a-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 b-amyloid peptide, A-b. Protection from MPP + was directly correlated with the preservation of mitochondrial function. Specifically, a-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, a-synuclein protected cells from the complex I inhibitor rotenone and 3-nitroproprionic acid, a complex II inhibitor. Wildtype a-synuclein-mediated neuroprotection and subsequent alterations in energy were not found in dbcAMP-differentiated cells. These results suggest that the normal physiological role for a-synuclein may change during development.

Dopamine-related and caspase-independent apoptosis in dopaminergic neurons induced by overexpression of human wild type or mutant α-synuclein

“…The neuroprotective effect of WT a-syn and neurotoxic effect of mutant a-syn observed in this study were consistent with several other studies [17,18,27,28,37,38].…”

Cell Stress Induced by the Parkinsonian Mimetic, 6-Hydroxydopamine, is Concurrent with Oxidation of the Chaperone, ERp57, and Aggresome Formation

“…Surprisingly, we have not observed aggresome formation in previous studies in either MN9D cells or primary dopaminergic neurons. Nor did we observe aggresomes when the major component of Lewy bodies, ␣-synuclein, was overexpressed in either its wild-type or mutant forms (18). Whether the doughnut-shaped structures (see Fig.…”

Valproic Acid is Neuroprotective in the Rotenone Rat Model of Parkinson’s Disease: Involvement of α-Synuclein

“…A growing body of evidence, indeed, suggests that a-synuclein is a survival factor in neuronal cultures (Alves da Costa et al 2002;Seo et al 2002;Jensen et al 2003;Leng and Chuang 2006;Monti et al 2007). Furthermore, while contrasting results have been obtained regarding overexpression of a-synuclein on neurotoxicity toward nigral dopaminergic neurons in intact animals (Masliah et al 2000;Matsuoka et al 2001;Rathke-Hartlieb et al 2001;Kirik et al 2002;Yamada et al 2004), transgenic overexpression was neuroprotective against herbicide (paraquat)-induced degeneration of nigral neurons .…”