Multiple Routes of Motor Neuron Degeneration in ALS

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurological disorder with higher selectivity in the degeneration of the upper and lower motor neurons, which leads to progres‐ sive paralysis of voluntary muscles. Although most cases fall under sporadic ALS (sALS), 10% of cases are inherited and known as familial ALS (fALS). The etiology of most ALS cases remains unknown, but mutations of ALS-linked Cu/Zn superoxide dismutase 1 (SOD1) are the most common causes of fALS and are responsible for its neurotoxicity and disease propagation due to the acquired toxic gain-of-function [1-2]. Studies in both human ALS patients and the transgenic ALS mouse model have delineated multiple pathological mecha‐ nisms of neuronal death that include genetic mutations, excitotoxicity, free radicals, apoptosis, inflammation, and protein aggregation. Targeting the multiple routes of the motor neuron degeneration is likely to contribute to the development of novel therapeutics for ALS patients.