The basic mechanisms that underlie neurodegenerative diseases are unknown. Loss of function of specific regions of the brain is due to incapacitation of cells that constitute the specialized regions. Cells can simply stop functioning normally - neurons may cease to transmit signals - or they may die. There is now evidence that the pathology of several neurodegenerative diseases is due to inappropriate cell death, specifically, adventitious activation of apoptosis. This being the case, an understanding of the mediators of apoptosis, their identities and their role in orchestrating death, would be a vital step towards remedying the diseases. The apoptotic system is mediated by proteolytic enzymes that are responsible for conducting faithful execution of all responsive human cells. We propose to study neuronal apoptosis, and the proteolytic systems that contribute to it, in a simplified model that can be manipulated to answer basic issues of cell death pathways. The object of this proposal is to understand fundamental processes of cell death in cell culture models of human neurons and in primary rodent neurons. Specifically, we will focus on the pathways to apoptosis involving caspase family proteases in cell-free models of neuronal differentiation based on the neuronal-derived SHSY5Y cell line. We will use the knowledge gathered from these studies to examine apoptosis in rodent models of neuronal apoptosis, and specifically test the hypothesis that neuronal plasticity is in part due to activation of a localized apoptotic, protease-mediated program. ? ?
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