Protein Aggregates in Pathological Inclusions of Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that is characterized by a progressive loss of upper and/or lower motor neurons (Bruijn et al., 2004). Dysfunction and death of these neurons lead to muscle weakness, atrophy and spasticity. A fatal event for the majority of patients is a failure of the respiratory muscles, which generally occurs within one to five years of disease onset. The typical age of onset is between 50 and 60 years, and the prevalence rate is 5 – 10 cases per 100,000 populations (de Belleroche et al., 1996). No effective cures for this disease are currently available, and the pathomechanism still remains controversial. The majority of ALS cases have no genetic component (sporadic ALS, sALS), while about 10 % are inherited in a dominant manner (familial ALS, fALS). Historically, ALS has been described by Charcot and Joffroy in 1869 (Charcot & Joffroy, 1869), and linkage analysis of fALS families was performed in 1991, by which the genetic locus was identified to be linked to chromosome 21q (Siddique et al., 1991). In 1993, Rosen et al. (Rosen et al., 1993) and Deng et al. (Deng et al., 1993) have found that mutations in the Cu,Zn-superoxide dismutase (SOD1) gene, which lies on chromosome 21q, are associated with fALS. Because SOD1-related fALS exhibited several clinicopathological similarities to sALS, various animal models including rodents, worms and flies have been constructed, in which mutant forms of SOD1 are expressed. Using these models, furthermore, various drugs have been continuingly tested to cure or alleviate ALS. In 2001, ALS2 (or called alsin) has been also identified as a new gene associated with a rare, recessively inherited and slowly progressed juvenile onset form of ALS, which is, however, significantly different from the disease phenotypes of sALS (Hadano et al., 2001; Yang et al., 2001). Accordingly, studies on mutant SOD1 have served as a “gold standard” for a long time and provided valuable insight into molecular pathomechanisms of ALS. Recent progress on genetic analysis has fuelled the identification of other genes responsible for fALS: for example, TAR DNA-binding protein-43 (TDP-43) gene reported in 2008 (Gitcho et al., 2008; Kabashi et al., 2008; Sreedharan et al., 2008; Van Deerlin et al., 2008), Fused in Sarcoma (FUS) gene in 2009 (Kwiatkowski et al., 2009; Vance et al., 2009). Each of TDP-43 and FUS mutations describes approximately 4 % of total fALS cases, which is a smaller number than that of SOD1 mutations (~20 % of total fALS cases). Unlike SOD1, however, TDP-43 and/or FUS pathologies are observed in many of sALS patients (Deng et al., 2011b; Mackenzie et al., 2007) and also in other neurodegenerative diseases (Lagier-