3.2 Amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS), which occurs in middle age, is a progressive disease characterized by the degeneration of motor neurons in the primary motor cortex, brain stem and spinal cord. ALS is also a neurodegenerative disorder and little is known about the underlying mechanism of ALS in most patients, but many genes were reported to cause familial ALS (FALS), such as SOD1 (the first ALS gene to be identified in 1993), TBK1 , SQSTM1 , etc .(Rosen, 1993; Fecto et al. , 2011; Freischmidt et al. , 2015).In 2010, Maruyama H et al . identified OPTN  as a causative gene for amyotrophic lateral sclerosis for the first time and found three types of mutations: a homozygous deletion of exon 5, a homozygous Q398X nonsense mutation and a heterozygous E478G missense mutation which is within its ubiquitin-binding domain (Maruyama et al. , 2010). Different from E50K, the role of E478G cause autophagy dysfunction seems none controversial. Before long, another novel missense mutation, Q454E, located in UBD domain of OPTN that causing ALS is reported (van Blitterswijk et al. , 2012). Same as the E478G, Q454E shows impaired mitophagy after CCCP treatment in Hela cells (Chernyshovaet al. , 2019). We focus here on E478G of OPTN, since this is the mutation in UBD domain of OPTN in which autophagy has been most studied. Although the direct connection between ALS and defective autophagy caused by E478G is not confirmed, the E478G mutation severely affects autophagy, which involved in many aspects of autophagy.
Mutation of E478G is located in UBAN domain of OPTN which abolishes the binding to ubiquitin (Wild et al. , 2011). Wonget al . first find that E478G OPTN mutation disrupts autophagosome recruitment which arouse the importance of UBDN domain to OPTN in autophagy. As they find that OPTN siRNA-depleted Hela cell reduce the capacity to recruit LC3 to mitochondria together with the slower rates of autophagosome formation after CCCP treatment (Wong et al. , 2014). A more precise mechanism was reported that the mutation of E478G, as well as Q398X, disrupted the association of OPTN with Myosin VI. As we review above, the association of OPTN and Myosin VI facilitated in autophagosome maturation, which is an indispensable process in autophagy. Similar biological process have also been reported by Bansal et al (Bansal et al. , 2018). They find E478G mutation impairs the ability of OPTN to form autophagosomes probably because of it disrupt the complex formation between OPTN and Atg12-5 conjugate, and then it had an effect in the recruitment of Atg12-5-16L1 complex to Wipi2-positive structures. They also found E478G OPTN mutation showed little co-localization with myosin VI which inhibiting autophagosome–lysosome fusion. Although the mechanism of E478G affecting autophagy has been well studied, there is still no direct evidence that OPTN mutations lead to autophagy defects is a direct factor in the pathogenesis of ALS. In order to figure out the causality, E478G combined with autophagy inducer is worth a try.
In view of current drug therapies for ALS can only offer a slightly clinical benefit for patients and a mild improvement in survival, OPTN-targeting drug may be a promising treatment strategy.