Decoding Amyotrophic Lateral Sclerosis: A Systems Biology Approach

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the loss of upper and lower motor neurons in the motor cortex, brain stem, and the anterior horn of the spinal cord. The majority of ALS cases are classified as sporadic (sALS). There is a growing concern regarding the increased incidence in the number of sporadic ALS cases across the world, projected to increase by almost 70% in the next two decades. The etiology of sporadic ALS is currently unknown; however, epidemiological studies point to possible exposure of environmental triggers, including trauma and infections as risk factors for the development of motor neuron pathology. On a pathological basis, protein misfolding with the accumulation of cytoplasmic inclusions of TDP-43 are regarded as the hallmark feature of ALS pathogenesis. The cellular mechanisms that lead to protein aggregation are not completely understood, but appear to involve defects in autophagy, an intracellular autodigestive process that degrades misfolded proteins like TDP-43. This review will be split into two portions: (1) discuss the evidence regarding how various environmental risk factors, such as infections agents and physical trauma, can lead to neuropathological changes by disrupting autophagy in ALS; (2) discuss potential treatment options in the management of each environmental factor previously discussed.