Amyotrophic Lateral Sclerosis

Abstract Amyotrophic lateral sclerosis is a progressive neurodegenerative syndrome characterized by loss of motor neurons. Cognitive impairment occurs in a significant proportion of those affected. Numerous theories of pathogenesis have been advanced. The most cogent hypothesis is that genetic susceptibilities to neurodegeneration interact with environmental exposures, leading to neuronal injury, glial activation and neuronal death. Modern tools of molecular and cell biology and constructive international collaborations have provided insights into the factors that increase disease susceptibility. The important observation that genes associated with ribonucleic acid (RNA) processing are implicated in disease pathogenesis will undoubtedly influence the direction of research in the coming years. These factors, combined with improvements in clinical trial design, and an improved understanding of the limitations of translating positive findings from animal models to human subjects, are likely to lead to new and successful therapeutic options for patients in the near future. Key concepts: Amyotrophic lateral sclerosis is a motor system degeneration. The incidence of amyotrophic lateral sclerosis is relatively uniform in populations of European ancestry. Disease frequency is lower in populations of mixed ancestry. Amyotrophic lateral sclerosis (ALS) is associated with cognitive decline in up to 50% of cases, and with dementia in up to 20%. There is an acknowledged clinical, imaging, neuropathologic and neurogenetic overlap between ALS and frontotemporal dementia. Amyotrophic lateral sclerosis is a complex genetic condition, in which genetic susceptibility interacts with environmental exposures to produce a neurodegenerative cascade. The progression of amyotrophic lateral sclerosis is due in part to the activation of glia, which contributes to the process of neurodegeneration. Recent genetic studies of amyotrophic lateral sclerosis have implicated genes involving RNA regulation, including transcription, RNA splicing, RNA transport and translation.