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Patricia K. Sonsalla
Professor
UMDNJ-RWJMS
Department of Neurology
Staged Research Bldg, Room 142
661
Hoes Lane
Piscataway. NJ 08854
(732) 235-4065
FAX - 5295
sonsalla@umdnj.edu |
Neurodegeneration. models of Parkinson's Disease. mechanisms of cell
death. synaptic vesicles and neurotransmitter transporters as modulators of
neurotoxin damage
The goal of our research is to gain an understanding of neurodegeneration. particularly of the nigrostriatal dopaminergic neurons that are destroyed in
Parkinson's disease. and to develop pharmacological strategies to prevent cell
death. Present research focuses on the roles of mitochondria. synaptic vesicles. the neurotransmitter transporters and the neurotransmitter dopamine in
neurodegeneration. We have found that vesicles within dopaminergic neurons may
act as storage sites for the dopaminergic neurotoxin. 1-methyl-4-phenylpyridinium. thus reducing its toxicity. Conversely. we have
discovered that when vesicles are disrupted and dopamine is displaced into the
cytosol. especially under conditions of a metabolic stress such as that created
by mitochondrial inhibitors. neuronal damage is intensified. This enhanced
toxicity may derive from an increase in dopamine oxidation products within the
cytosol. Additionally. we have observed a rapid loss of vesicle function in
vivo following exposure to neurotoxins. It is not known if this phenomenon
reflects a primary step in neurodegeneration or is a consequence of an oxidative
stress. but demonstrates the early disruption of a cellular organelle critical
for maintaining neuronal activity.
In vitro cell culture models. isolated vesicle preparations and in
vivo studies with brain infusion and microdialysis techniques are used in
our research. A current research aim is to examine whether other neurotoxins may
be sequestered into the vesicles. Other aims will investigate the role of
dopamine and its oxidation products in neurodegeneration and assess various
pharmacological agents for their ability to provide protection against cell
death. Additionally. we will examine a number of drugs or environmental
substances that disrupt vesicular function and displace dopamine from vesicles
for their propensity to exacerbate damage during toxic insult and stressful
conditions.
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