Aberrant Mitochondrial Handling of Calcium in ALS

University Of Miami School Of Medicine, Coral Gables FL

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Abstract

[unreadable] DESCRIPTION (provided by applicant): This project will study the role of abnormal mitochondrial function in motor nerve terminals in the pathogenesis of amyotrophic lateral sclerosis (ALS). Mitochondria take up cytosolic Ca2+ during repetitive stimulation at mouse motor nerve terminals. Studies have detected abnormalities in mitochondrial Ca2+ handling and abnormal mitochondrial depolarizations following repetitive stimulation of motor terminals in a mouse model for ALS: Stimulation-induced changes in mitochondrial [Ca2+] and in mitochondrial membrane potential using fluorescent indicator dyes and confocal microscopy will be measured. Proposed experiments will compare mutant and wild-type mice, and also carry out these measurements in normal mice with partially inhibited electron transport chain activity, one of the proposed mechanisms for ALS pathogenesis. Young mice that have yet to develop signs of disease will be used and compared to previous results from older, affected mice. Finally, the degree of denervation of motor end-plates after marked neuronal activity will be measured with fluorescent markers for both the nerve terminal cytoplasm and the muscle end-plate. [unreadable] [unreadable]