Fas (CD95)-induced regeneration of dopaminergic neurons

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Parkinson's disease is characterized by the degeneration of dopamine- producing neurons in the substantial nigra of the brain. The resulting loss of dopamine leads to the cardinal symptoms of Parkinson's disease (PD), namely tremor, bradykinesia, postural instability, and rigidity. The disease is relentlessly progressive, ultimately resulting in a state of almost complete disability. Although PD can be slowed by current treatment protocols, it cannot be cured nor prevented at present. We have recently found that stimulating the cell surface molecule (Fas (CD95) on peripheral sensory neurons induces rapid, extensive neurite outgrowth in vitro, and can accelerate functional recovery in vivo after sciatic nerve crush injury. Contrary to the traditional view of Fas as a "death receptor", we propose that Fas engagement may induce regeneration of the dopaminergic neurons. In support of this notion, PD patients have elevated levels of soluble Fas in the substantial nigra. Soluble Fas acts as decoy receptor to prevent cell surface Fas from being engaged. Furthermore, mice with reduced Fas expression undergo progressive neural degeneration, and exhibit neurological and cognitive deficits. We propose to investigate the causal relationship between Fas expression and PD through the following specific aims: 1. To determine the physiological effects, and the signaling pathway(s) triggered, by Fas engagement on dopaminergic neurons. 2. To determine whether lack of Fas expression predisposes dopaminergic neurons to degeneration and/or MPTP toxicity (a model for PD). 3. To establish if anti-Fas antibody can stimulate dopaminergic neuron recovery in vivo. To accomplish these aims, we will use three models: tyrosine hydroxylase-positive (TH+) cell lines; in vitro cultures of embryonic mouse ventral mesencephalon cells enriched for TH+ neurons by flow cytometric sorting; and MPTP- induced nigrostriatal degeneration in the mouse as an in vivo model of PD. We will design our experiments to test the novel concept that Fas is able to induce regeneration in CNS neurons. The successful completion of these aims would yield a conceptually novel direction in the study of PD and neurodegenerative diseases in general, and a new target for innovative treatment strategies.