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Cu/Zn Superoxide Dismutase Typical for Familial Amyotrophic Lateral Sclerosis Increases the Vulnerability of Mitochondria and Perturbs Ca²⁺ Homeostasis in SOD1^G93A Mice

Center of Physiology, Georg-August University, Goettingen, Germany

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective loss of defined motoneuron populations in the brainstem and spinal cord. Although low cytosolic calcium ([Ca²⁺]_i) buffering and a strong interaction between metabolic mechanisms and [Ca²⁺]_i have been associated with selective motoneuron vulnerability, the underlying cellular mechanisms are barely understood. To elucidate the underlying molecular events, we used rapid charge-cooled device imaging to evaluate Ca²⁺ signaling and metabolic signatures in the brainstem slices of SOD1^G93A mice, the mouse model of human ALS, at 8 to 9 and 14 to 15 weeks of age, corresponding to the presymptomatic and symptomatic stages of motor dysfunction, respectively, and compared the results with corresponding age-matched wild-type littermates. We also monitored the mitochondrial membrane potential (_m) of brainstem motoneurons, a valuable tool for characterizing the metabolic signature of intrinsic energy profiles and considered to be a good experimental measure for monitoring energy metabolism in cells. We found that different pharmacological interventions substantially disrupt _m in SOD1^G93A motoneurons during the symptomatic stage. Furthermore, we investigated the impact of impaired mitochondrial mechanisms on [Ca²⁺]_i regulation by using the membrane-permeable indicator fura-acetoxy methyl ester. Taken together, the results indicate that mitochondrial disruptions are critical elements of SOD1^G93A-mediated motoneuron degeneration in which selective motoneuron vulnerability results from a synergistic accumulation of risk factors, including the disruption of electrochemical potential, low Ca²⁺ buffering, and strong mitochondrial control of [Ca²⁺]_i. The stabilization of mitochondria-related signal cascades may represent a useful strategy for clinical neuroprotection in ALS.

Received for publication August 9, 2008.

Accepted for publication December 4, 2008.

Address correspondence to: Dr. Bernhard U. Keller, Center of Physiology, University of Goettingen, Humboldtallee 23, 37073, Goettingen, Germany. E-mail: bkeller1{at}gwdg.de