Molecular mechanisms and animal models of spinal muscular atrophy

AbstractSpinal muscular atrophy (SMA), the leading genetic cause of infant mortality, is characterized by the degeneration of spinal motor neurons and muscle atrophy. Although the genetic cause of SMA has been mapped to the Survival Motor Neuron1 (SMN1) gene, mechanisms underlying selective motor neuron degeneration in SMA remain largely unknown. Here we review the latest developments and our current understanding of the molecular mechanisms underlying SMA pathogenesis, focusing on the animal model systems that have been developed, as well as new diagnostic and treatment strategies that have been identified using these model systems. This article is part of a special issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis

Impaired Autophagy and Defective Mitochondrial Function: Converging Paths on the Road to Motor Neuron Degeneration in ALS

Selective motor neuron degeneration is a hallmark of amyotrophic lateral sclerosis (ALS). Around 10 percent of all cases present as familial ALS (FALS), while sporadic ALS (SALS) accounts for the remaining 90 percent. Diverse genetic mutations leading to FALS have been identified, but the underlying causes of SALS remain largely unknown. Despite the heterogeneous and poorly understood etiology, different types of ALS exhibit overlapping pathology and common phenotypes, including protein aggregation and mitochondrial deficiencies. Here we review the current understanding of mechanisms leading to motor neuron degeneration in ALS, as they pertain to disrupted cellular clearance pathways, ATP biogenesis calcium buffering and mitochondrial dynamics. Through focusing on impaired autophagic and mitochondrial functions, we highlight how the convergence of diverse cellular processes and pathways contributes to common pathology in motor neuron degeneration