The Genetics of Amyotrophic Lateral Sclerosis: Current Insights

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that results in loss of the upper and lower motor neurons from motor cortex, brainstem and spinal cord. Whilst the majority of cases are sporadic, around 10% show familial inheritance. ALS is usually inherited in an autosomal dominant manner, though autosomal recessive and X-linked inheritance do occur. To date, 24 of the genes at 26 loci have been identified; these include loci linked to ALS as well as to FTD-ALS, where family pedigrees contain individuals with frontotemporal dementia with/without ALS. The most commonly established genetic causes of FALS to date are the presence of a hexanucleotide repeat expansion in the C9ORF72 gene (39.3% FALS) and mutation of SOD1, TARDBP and FUS, with frequencies of 12-23.5%, 5% and 4.1% respectively. However, with the increasing use of next generation sequencing of small family pedigrees, this has led to an increasing number of genes associated with ALS. This review provides a comprehensive review on the genetics of ALS and an update of the pathogenic mechanisms associated with these genes. Commonly implicated pathways have been established, including RNA processing, the protein degradation pathways of autophagy and ubiquitin-proteasome-system as well as protein trafficking and cytoskeletal function. Elucidating the role genetics plays in both FALS and SALS is essential for understanding the subsequent cellular dysregulation that leads to motor neuron loss, in order to develop future effective therapeutic strategies.