Parkinson's disease is a debilitating motor impairment disorder due to loss of nigral dopamine neurons. Mitochondrial defects in PD patients implicate energy impairment and metabolic stress as potential factors in its etiology. Moreover, DA oxidation products may add to the oxidative burden within DA neurons which, coupled with a persistent metabolic stress, may lead to neurodegeneration. Epidemiological studies link PD with environmental exposure to substances such as pesticides. - Many pesticides are mitochondrial inhibitors. A potential form of protection against mitochondrial toxins (i.e., MPP+) may be their sequestration into synaptic vesicles of DA neurons. The goal of this project is to gain an understanding of the role of vesicles, the vesicular monoamine transporter (VMAT2) and DA in modulating neurodegeneration produced by mitochondrial toxins. One hypothesis is that the actions of mitochondrial toxins can be modulated in contrasting ways depending on whether the toxins are sequestered into vesicles. If sequestered, toxin exposure could be abrogated. In contrast, disruption of vesicular function toxin could lead to disturbed DA homeostasis and enhanced toxicity since it would remove the toxin from interaction with mitochondria.
In Aim 1 several mitochondrial toxins will be examined for their ability to interfere with vesicle function (i.e. to inhibit DA uptake into isolated rat membrane vesicles).
In aim 2, rat mesencephalic cultures or rat striata will be exposed to mitochondrial toxins following VMAT2 inhibition to determine if toxicity is modified. To examine the hypothesis that disturbed DA homeostasis contributes to degeneration produced by metabolic stress, two approaches will be used. First, DA will be depleted prior to exposure of culture or rat striata to a mitochondrial inhibitor. Second, vesicle contents (DA) will be released into the cytosol after exposure to the mitochondrial toxin to examine if augmented disruption of DA homeostasis during the metabolic stress enhances toxicity. Additionally, the hypothesis that substances that are not themselves mitochondrial inhibitors, but can disrupt DA storage in vesicles may amplify damage during episodes of metabolic stress will be examined in Aim 3.
In aim 4 the hypothesis that early events such as oxidative stress leads to loss of vesicle function, disruption of DA homeostasis and exacerbation of neurodegeneration produced by toxins will be investigated. Isolated vesicles will be tested for their sensitivity to oxidizing and reducing conditions. Results from these studies will provide novel and relevant information as to the contribution of VMAT2 containing vesicles in neuroprotection as well as in neurodegeneration of DA neurons during metabolic stress.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS041545-02
Application #
6540439
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Project Start
2001-04-01
Project End
2005-03-31
Budget Start
2002-04-01
Budget End
2003-03-31
Support Year
2
Fiscal Year
2002
Total Cost
$302,600
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Neurology
Type
Schools of Medicine
DUNS #
622146454
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
Sonsalla, Patricia K; Zeevalk, Gail D; German, Dwight C (2008) Chronic intraventricular administration of 1-methyl-4-phenylpyridinium as a progressive model of Parkinson's disease. Parkinsonism Relat Disord 14 Suppl 2:S116-8
Meredith, Gloria E; Sonsalla, Patricia K; Chesselet, Marie-Francoise (2008) Animal models of Parkinson's disease progression. Acta Neuropathol 115:385-98
Moy, Lily Y; Wang, Sheng-Ping; Sonsalla, Patricia K (2007) Mitochondrial stress-induced dopamine efflux and neuronal damage by malonate involves the dopamine transporter. J Pharmacol Exp Ther 320:747-56
Yazdani, U; German, D C; Liang, C-L et al. (2006) Rat model of Parkinson's disease: chronic central delivery of 1-methyl-4-phenylpyridinium (MPP+). Exp Neurol 200:172-83
Alfinito, Peter D; Wang, Sheng-Ping; Manzino, Lawrence et al. (2003) Adenosinergic protection of dopaminergic and GABAergic neurons against mitochondrial inhibition through receptors located in the substantia nigra and striatum, respectively. J Neurosci 23:10982-7