CALCIUM SIGNALING AND CELL DEATH IN CELLULAR MODELS OF ALZHEIMER AND PARKINSON'S

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Neurodegenerative syndromes such as Alzheimer's (AD) and Parkinson's (PD) diseases are characterized by the selective, inappropriate death of specific central neurons. The disease are prevalent, progressively devastating, and costly of human lives and health care dollars. Current treatments are primarily symptomatic and do not health disease progression. Understanding the cellular basis of selective neuronal vulnerability will hasten discovery of novel treatments. This project examines the biological consequences of mitochondrial DNA (mtDNA) defects of AD, comparing them to those of PD, by studying a model neural cell with mtDNA from patients. It is part of a Program Project organized to examine aspects of AD and mitochondrial function in relation to Alzheimer's disease. Selective neural vulnerability implies death results from an unique insult to the population, an exceptional phenotypic susceptibility to a general insult, or a combination. Mitochondria from AD and PD patients have electron chain defects that may combine with specific neuronal phenotypes and/or circumstances to yield enhanced vulnerability to cell death. The influence of AD and PD mtDNA upon sensitivity to induced cell death will be examined and compared in cybrid models and primary neuronal cultures. Most cell death events share certain features. Apoptosis is a process for neural removal via transcription-dependent cell death. Induction of apoptotic processes versus necrotic sequences will be distinguished and examined in the model cultures. The regulation of cytosolic Ca/2+ and generation of reactive oxygen species (ROS) are known to play central role sin triggering cell death. The influence of AD and PD mtDNA upon cell Ca/2+, Ca/2+ buffering performance and ROS production will be studied, using fluorescence assays and ratio fluorimetry in groups of cultured cells and in single, identified neurons. Neurotrophic growth factors have been shown to protect neurons from cell death in certain circumstances. The effects of these signal molecules on Ca/2+ handling and ROS production will be examined during rescue from cell death. The research goals are enhanced by inter-projected collaborations and comparisons measuring ETC activity, the cell death genetic program in the cybrid model neurons and alterations in free-radical generation in vivo. The results of these studies will define the specific cellular consequences of mtDNA defects in patients to the regulation of cell death in a model neuron background. Knowledge of the neural vulnerability conferred by the mtDNA will predict the best therapy to overcome the defects and circumvent or delay neural death.