Associate Provost for Research Boston University Medical Campus
NIEHS - National Institute of Environmental Health Sciences	Research Resources

Abstract

Abstract: DESCRIPTION (provided by applicant): The causes of Parkinson's disease (PD) are poorly understood, and so treatment is currently limited to palliative options. Studies of PD have identified both environmental and genetic factors that contribute to the pathophysiology of PD. We will investigate how three PD-related proteins, alpha-synuclein, parkin/KO8E3.7 (the C. elegans homologue of parkin) and DJ-1, affect the toxicity due to inhibition of complex I of the mitochondrial electron transport chain. We will mainly use rotenone as the model toxin for complex I disruption. The three PD-related proteins each have very different putative functions, and how these activities integrate with the pathophysiology of PD is poorly understood. Our preliminary data indicate that expressing alpha-synuclein or deleting KO8E3.7 increases oxidative damage and apoptosis induced by rotenone treatment in C. elegans. In addition, we have identified compounds, D-beta-hydroxybutyrate (a mitochondrial complex II stimulant), tauro-ursodeoxycholic acid (an anti-apoptotic bile acid) and probucol (a potent anti-oxidant), that each partially inhibit rotenone toxicity when applied alone, but in combination prevent rotenone toxicity in C. elegans. In this proposal, we will determine the mechanism of by which alpha- synuclein, parkin/KO8E3.7 and DJ-1 increase mitochondrial damage in both C. elegans and mammalian neurons (primary mouse neuronal cultures and the human neuronal BE-M17 line). We will also determine whether the treatment strategies identified in C. elegans protect mammalian neurons in vitro and in vivo. We hypothesize that mutations in PD-related genes destabilize the mitochondrial electron transport chain leading to an increased tendency to produce free radicals and activate apoptosis. We also hypothesize that combined use of agents that enhance electron transport and inhibit apoptosis (or oxidation) will protect neurons against degenerative processes associated with PD. Aim 1 will determine whether manipulation of PD-related genes inhibit mitochondrial or proteasomal function, and whether the sensitivity to inhibition increases with age. Aim 2 will determine whether manipulation of PD-related genes increase apoptosis during rotenone-induced toxicity. Aim 3 will determine whether combined use of a mitochondrial complex II stimulant plus an apoptotic inhibitor or antioxidant protects neurons against degeneration in transgenic mice carrying the A53T alpha-synuclein transgene..

Thesaurus Terms:
Parkinson's disease, alpha synuclein, cellular pathology, enzyme complex, gene environment interaction, gene mutation, mitochondrial disease /disorder, neural degeneration, neuropathology, oxidoreductase inhibitor, parkin gene /protein, plant insecticide
antioxidant, apoptosis, beta hydroxybutyrate, chenodeoxycholate, electron transport, genetic model, neuron, neuroprotectant, oxygen consumption, proteasome
Caenorhabditis elegans, RNA interference, cell line, genetically modified animal, laboratory mouse

Institution:	BOSTON UNIVERSITY MEDICAL CAMPUS
	715 ALBANY ST, 560
	BOSTON, MA 021182394
Fiscal Year:	2006
Department:	PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Project Start:	15-AUG-2006
Project End:	30-JUN-2011
ICD:	NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
IRG:	ZRG1