Ca2+, mitochondria and selective motoneuron vulnerability: implications for ALS

Motoneurons are selectively damaged in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. Although the underlying mechanisms are not completely understood, increasing evidence indicates that motoneurons are particularly sensitive to disruption of mitochondria and Ca2+ -dependent signalling cascades. Comparison of ALS-vulnerable and ALS-resistant neurons identified low Ca2+ -buffering capacity and a strong impact of mitochondrial signal cascades as important risk factors. Under physiological conditions, weak Ca2+ buffers are valuable because they facilitate rapid relaxation times of Ca (2+) transients in motoneurons during high-frequency rhythmic activity. However, under pathological conditions, weak Ca2+ buffers are potentially dangerous because they accelerate a vicious circle of mitochondrial disruption, Ca2+ disregulation and excitotoxic cell damage.