Abstract
Selective motor neuron degeneration is a hallmark of amyotrophic lateral sclerosis (ALS). Around 10% of all cases present as familial ALS (FALS), while sporadic ALS (SALS) accounts for the remaining 90%. Diverse genetic mutations leading to FALS have been identified, but the underlying causes of SALS remain largely unknown. Despite the heterogeneous and incompletely 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.
Highlights
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by loss of large motor neurons in the brain and spinal cord, resulting in progressive voluntary muscle wasting and respiratory failure
ALS was first described by Charcot as early as 1869 (Jay, 2000), it wasn’t until more than a century later that the first casual mutation was identified in copper zinc superoxide dismutase 1 (SOD1; Rosen, 1993)
Gain-of-function properties of disease-associated mutations can directly lead to protein aggregation (Sau et al, 2007; Johnson et al, 2008; Xu et al, 2013; Wu et al, 2014)
Summary
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by loss of large motor neurons in the brain and spinal cord, resulting in progressive voluntary muscle wasting and respiratory failure. Despite the heterogeneous and multigenic nature of ALS, overlapping pathology and common phenotypes are observed in different forms of the disease. Protein aggregates found in ALS patients suggest that cellular clearance mechanisms, such as the autophagy-lysosome pathway, Autophagic and Mitochondrial Dysfunction in ALS may be impaired in this disease (Blokhuis et al, 2013). Increased oxidative stress and compromised mitochondrial function are observed in ALS disease condition (Wang and Michaelis, 2010). Oxidative stress is a potent regulator of autophagy (Scherz-Shouval et al, 2007; Huang et al, 2011; Scherz-Shouval and Elazar, 2011), suggesting the potential for functional interactions between the lysosomal and mitochondrial pathways. We will consider in depth the dysregulation of autophagy and mitochondrial pathways, as well as their interactions in the context of ALS pathogenesis. We will discuss the role of oxidative stress as a critical regulator linking these discrete processes, and consider the therapeutic implications for ALS
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