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, develop improved therapies and identify transcription control mechanisms of genes that mediate dopaminergic neural transmission. Parkinson's disease is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta. A fundamental question in this and in many other neurodegenerative disorders is the selective vulnerability of unique neuronal populations in the brain. In the case of Parkinson's disease, this appears to be the result of multiple factors but most notably the production of the transmitter dopamine by nigral neurons. We have identified the molecular signaling pathway by which dopamine can result in apoptotic death. This is due to the fact that dopamine is an efficient generator of reactive oxygen species, leading to the activation of p38MAP kinase and JNK, which induce the release of cytochrome c from mitochondria. Subsequently, caspase 9 is cleaved (activated) leading to the activation of the final executor caspase 3. Towards our goal to develop novel therapeutic strategies for Parkinson's disease, we had previously found that the bone marrow contains cellular elements capable of seeding the brain and homing preferentially into injured tissue. We now sought to exploit these cells as vehicles to deliver a therapeutic gene to the brain, namely the genes that encodes the potent dopaminergic neurotrophic factor Glial Cell Line Derive Neurotrophic Factor (GDNF). We demonstrated that bone marrow transplantation with GDNF-engineered cells protects mice against the dopaminergic neurotoxin MPTP. Dopamine exerts its effects through its cell surface receptors, which are under complex spatial and temporal regulation. We found a novel zinc finger transcription factor, designated DRRF (Dopamine Receptor Regulatory Factor) which modulates the expression of these receptor genes. We also identified several specific transcription factor interactions that modulate the expression of dopamine receptor genes in neuronal cells. For example, Zic2 and Sp3 repress Sp1-mediated activation of the D1A dopamine receptor promoter and the TALE homeodomain proteins Meis2 and TGIF differentially regulate transcription.