Genetics of amyotrophic lateral sclerosis: an update

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder involving both upper motor neurons (UMN) and lower motor neurons (LMN). Enormous research has been done in the past few decades in unveiling the genetics of ALS, successfully identifying at least fifteen candidate genes associated with familial and sporadic ALS. Numerous studies attempting to define the pathogenesis of ALS have identified several plausible determinants and molecular pathways leading to motor neuron degeneration, which include oxidative stress, glutamate excitotoxicity, apoptosis, abnormal neurofilament function, protein misfolding and subsequent aggregation, impairment of RNA processing, defects in axonal transport, changes in endosomal trafficking, increased inflammation, and mitochondrial dysfunction. This review is to update the recent discoveries in genetics of ALS, which may provide insight information to help us better understanding of the disease neuropathogenesis.

Figure 1

ALS is caused by interplay of various molecular pathways in motor neurons and an interaction with neighbouring non-neuronal cells like microglia and astrocytes. Microglial cells activate an inflammatory cascade via secretion of cytokines. Astrocytes lead to motor neuron injury through release of inflammatory mediators such as nitric oxide and prostaglandin E2. Accumulation of superoxide radicals and oxidative stress, aberrant RNA processing, protein misfolding and insoluble proteins may cause motor neuron degeneration in ALS. Protein aggregation may lead to endoplasmic reticulum stress along with defective endosomal trafficking and mitochondrial damage, which may cause organelle disruption and activates autophagy and apoptotic pathways. Axonal transport abnormalities lead to energy deficiency in the axon along with the defective axonal growth and axonal dysfunction. Axonal dysfunction, defective angiogenesis and metabolic disturbance may contribute to motor neuron degeneration in ALS.