Patricia K. Sonsalla
Robert Wood Johnson Medical School
Department of Neurology
125 Paterson St.
New Brunswick, NJ 08901
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.