Selective vulnerability of motoneuron and perturbed mitochondrial calcium homeostasis in amyotrophic lateral sclerosis: implications for motoneurons specific calcium dysregulation

Abstract

Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disorder characterized by the selective degeneration
of defined subgroups of motoneuron in the brainstem, spinal cord and motor cortex 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+
]c) buffering and a
strong interaction between metabolic mechanisms and [Ca2+
]i have been identified predominantly in motoneuron
impairment, the causes of these disruptions are unknown. The existing evidence suggests that the mutant superoxide
dismutase1 (mtSOD1)-mediated toxicity in ALS acts through mitochondria, and that alteration in cytosolic and
mitochondria-ER microdomain calcium accumulation are critical to the neurodegenerative process. Furthermore,
chronic excitotoxcity mediated by Ca 2+ -permeable AMPA and NMDA receptors seems to initiate vicious cycle of
intracellular calcium dysregulation which leads to toxic Ca 2+ overload and thereby selective neurodegeneration.
Recent advancement in the experimental analysis of calcium signals with high spatiotemporal precision has
allowed investigations of calcium regulation in-vivo and in-vitro in different cell types, in particular selectively
vulnerable/resistant cell types in different animal models of this motoneuron disease. This review provides an
overview of latest advances in this field, and focuses on details of what has been learned about disrupted Ca 2+
homeostasis and mitochondrial degeneration. It further emphasizes the critical role of mitochondria in preventing
apoptosis by acting as a Ca 2+ buffers, especially in motoneurons, in pathophysiological conditions such as ALS.