Motoneuron specific calcium dysregulation and perturbed cellular calcium homestasis in amyotrophic lateral sclerosis: Recent advances gained from genetically modified animals and cell culture models

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective loss of defined subgroups of motoneuorn populations in the brainstem and spinal cord with signature hallmarks of mitochondrial Ca²⁺ overload, free radical damage, excitotoxicity and impaired axonal transport. Although intracellular disruptions of cytosolic and mitochondrial calcium and in particular low cytosolic calcium ([Ca²⁺]_i) buffering and a strong interaction between metabolic mechanisms and [Ca²⁺]_i have been associated with selective motoneuron degeneration, the underlying mechanisms are not well understood. The present evidence supports a hypothesis that mitochondria are a primary target of mutant superoxide dismutase1 (mtSOD1)-mediated toxicity in ALS and intracellular alterations of cytosolic and mitochondria-ER microdomain calcium accumulation might aggravate the course of this neurodegenerative disease. Furthermore, chronic excitotoxicity mediated by Ca²⁺- permeable AMPA and NMDA receptors seems to initiate a vicious cycle of intracellular calcium dysregulation which leads to toxic Ca²⁺ overload and thereby selective neurodegeneration. Recent advancement in the experimental analysis of calcium signals at high spatiotemporal precision has allowed investigations of calcium regulation in different cell types, in particular selectively vulnerable/resistant cell types in different animal models of this motoneuron disease. This chapter provides an overview of recent advances in this field and discusses in detail what has been learned about Ca²⁺ homeostasis and the role of mitochondria in motoneurons in pathophysiological conditions such as ALS.