Molecular Pathogenesis Of Cell Death In Neurodegenerativ

Neurological Disorders And Stroke

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Abstract

The goal of this project is to elucidate the molecular mechanisms by which nerve cells degenerate in Parkinson's disease and related neurodegenerative disorders, identify transcription control mechanisms that contribute to the pathogenesis of these diseases, and develop improved therapies. Parkinson's disease (PD) is characterized by progressive loss of dopaminergic neurons in the substantia nigra. A leading biochemical hypothesis that could account for this neuronal loss is the state of oxidative stress that these neurons are subjected to as a result of the biochemical milieu in the nigra and the metabolism of dopamine. Alpha-synuclein is mutated in few families with dominantly inherited PD and is a major fibrillar component of Lewy bodies. We found that over-expression of alpha-synuclein increases intracellular levels of reactive oxygen species and, thus, enhances their susceptibility to the apoptotic effects of dopamine. These deleterious effects of alpha-synuclein are pronounced by its PD-causing mutations. Our observations provide a link between mutations or expression level of alpha-synuclein and oxidant induced neuronal death. As part our long-standing interest in gene transcription and its role in physiologic brain functions and pathologic consequences, we found that huntingtin interacts with the transcription factor Sp1 and coactivator TAFII130. Soluble mutant huntingtin inhibits Sp1 binding to DNA in postmortem brain tissues of both presymptomatic and affected Huntingtin?s disease (HD) patients, and inhibits transcription from the D2 dopamine receptor promoter. Co-expression of Sp1 and TAFII130 reverses this transcriptional repression and protects neurons from huntingtin-induced toxicity. These early molecular events in HD could provide potential therapeutic targets. Another link between neurodegeneration and altered transcription came from our finding that poly-glutamine binding protein-1 (PQBP-1), which we had discovered earlier, interacts with ataxin-1 resulting in apoptosis. Mutant ataxin-1 with an expanded poly-glutamine tract, responsible for spinocerebellar ataxia-type 1, enhances the binding of PQBP-1 to RNA polymerase II leading to reduced transcription. This further supports the idea that modified transcription underlies polyglutamine mediated neuropathology. Towards our goal to develop novel therapeutic strategies for central nervous system disorders, we previously found that the bone marrow contains cellular elements capable of seeding the brain and homing preferentially into injured tissue. We also demonstrated that these cells can be exploited as vehicles to deliver the gene encoding for the neurotrophic factor Glial Cell Line Derived Neurotrophic Factor (GDNF) and can protect mice against the dopaminergic neurotoxin MPTP. We now confirmed the ability of bone marrow cells to deliver another gene product of therapeutic value in brain diseases, namely interferon-beta. Further refinements in this technology are underway.