Molecular Neurotoxicological Models Of Parkinsonism

National Institute On Drug Abuse

Investigators

Linked publications, trials & patents

Abstract

Parkinson's disease is a neurodegenerative disorder that affects mainly the nigrostriatal dopaminergic system in humans. Several propositions have been put forward to explain the cellular and molecular pathobiology of this syndrome. Initial attempts were made through the use of various agents to manipulate the deleterious effects of toxins that destroy dopaminergic cells both in vitro and in vivo. These studies led to the idea that oxidative stress is an important factor in killing these cells. Our laboratory has used various models of Parkinson's disease using 6-hydroxydopamine (6-OHDA), methamphetamine (METH), and MPTP to assess the role of various gene products in causing the neurodegeneration of DA systems. We have shown that mice that overexpress superoxide dismutase are protected against the toxicity of all three agents. We have shown, in addition, that the toxicity of METH and MPTP depend on p53 upregulation because p53 knockout mice are protected against METH toxicity while drugs that antagonize the effects of p53 also protect against MPTP-induced damamge. More recently, we have cDNA array analyses to assess the effects of METH on the regulation of various transcripts in the mouse brain. These investigations identify a number of pathways that are known to be involved in inflammatory processes and in causing apoptosis. Of significant interest are observations that METH can cause changes in the epxression of trophic factors and DNA repair proteins in the brain. These are novel findings that promise to revolutionize the approach to the understanding of pathways that are involved in causing Parkinson's disease. Ongoing studies in the laboratory will attempt to identify genes that are also regulated by MPTP and 6-OHDA in order to find common transcripts between these models. This approach will help to better characterize the molecular bases of DA system degeneration in Parkinsonism.