Disease Mechanisms Implicated in ALS
A wide range of cellular pathways have been implicated in ALS pathogenesis, as reviewed recently (Shin and Lee, 2013; Taylor et al., 2016; Balendra and Isaacs, 2018). These include altered RNA processing/metabolism, nucleolar dysfunction, RNA splicing transcriptional defects (Barmada, 2015; Fratta and Isaacs, 2018) and DNA damage (Konopka and Atkin, 2018; Penndorf et al., 2018). Proteostasis pathways have also been implicated, with impairments in autophagy and lysosomal function, the endoplasmic reticulum (ER), mitochondrial and the ubiquitin–proteasome systems described (Maharjan and Saxena, 2016; Ruegsegger and Saxena, 2016). Furthermore, several modes of vesicular trafficking are impaired in ALS, including nucleocytoplasmic (Kim and Taylor, 2017), ER-Golgi (Soo et al., 2015), and axonal forms of transport (De Vos and Hafezparast, 2017). In addition, defects in neuronal-specific processes, including hyper-excitability and hypo-excitability, glutamate excitotoxicity, and neuronal branching defects, have also been described in ALS (Fogarty, 2018).