P4HB and amyotrophic lateral sclerosis: That increased expression of PDIs in ALS represents an attempt to protection from toxic aggregates is further suggested by studies in vitro demonstrating that overexpression of PDI reduces mutant SOD1 inclusions, whereas silencing PDI expression increases their number, and that treatment of neuronal cells with (+/−)trans-1,2-bis(mercaptoacetamido)cyclohexane, an agent that mimics PDI activity, reduces mutant SOD1 inclusions in a dose-dependent manner (Walker et al., 2010; Jeon et al., 2014).