The fraction of soluble misfolded SOD1 was quantified with hydrophobic interaction chromatography (HIC) (Zetterstrom et al.,2007). least in part, from the propensity of this protein to misfold. In the wild-type SOD1 protein, nongenetic perturbations such as metal depletion, disruption of the quaternary structure, and oxidation, can also induce SOD1 to misfold. In fact, these aforementioned post-translational modifications cause wild-type SOD1 to adopt a toxic conformation that is similar to familial ALS-linked SOD1 variants. These observations, together with the detection of misfolded wild-type SOD1 within human post-mortem sporadic ALS samples, have been used to support the controversial hypothesis that misfolded forms of wild-type SOD1 contribute to sporadic ALS pathogenesis. In this review, we present data from the literature that both support and contradict this hypothesis. We also discuss SOD1 as a potential therapeutic target for both familial and sporadic ALS. Keywords:amyotrophic lateral sclerosis (ALS), sporadic amyotrophic lateral sclerosis, SOD1, protein misfolding, immunotherapy == Introduction == Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease and is clinically characterized by the degeneration of motor neurons in the brain and spinal cord, culminating in paralysis and death within 25 years. The only available treatment is riluzole, which in the best cases extends survival by only a few months (Glicksman,2011). In 1993, mutations in theSOD1gene encoding Cu,Zn superoxide dismutase-1 were reported as the first genetic link to familial, RKI-1313 or inherited, forms of ALS (FALS) (Rosen et al.,1993). Because of the high incidence ofSOD1mutations, which account for 2025% of FALS cases,SOD1has been one RKI-1313 of the most intensely studied genes in the ALS field and continues to be a primary therapeutic target (Bosco and Landers,2010). Much of what we understand about the pathomechanisms of ALS is based onin vivostudies with transgenic rodent models expressing FALS-linked SOD1 variants. These FALS-SOD1 animal models recapitulate many key features of the human disease, including motor neuron degeneration, paralysis and shortened life-span (Turner and Talbot,2008). Moreover, FALS-SOD1 animal models reveal the complex nature of this disease, which involves oxidative stress, a loss of proteostasis (i.e., protein aggregation with defective protein clearance), mitochondrial dysfunction, impaired axonal transport, and glutamate excitotoxicity (Rothstein,2009). While motor neurons are the primary target in ALS, ALS may actually represent a non-cell autonomous disorder for which glia play an active role (Ilieva et al.,2009). Despite decades of research on FALS-SOD1in vitroandin vivo, the exact mechanism of SOD1 in ALS pathogenesis remains unknown (Pasinelli and Brown,2006; Ling et al.,2013). However, as will be discussed throughout this review, a substantial body of literature points to a gain of toxic function for FALS-SOD1 that stems, at least in part, from SOD1 misfolding. In contrast to FALS, much less is known about the etiology of sporadic ALS (SALS), which accounts for 90% of ALS cases. Pathological aggregates composed of the TAR DNA-binding protein 43 (TDP-43) are detected in CNS tissues for a majority of SALS cases (Neumann et al.,2006), providing strong RKI-1313 evidence for an association of misfolded TDP-43 with ALS pathogenesis (Xu,2012). Mutations in TDP-43 RKI-1313 have also been linked to SALS and FALS (Sreedharan et al.,2008), further establishing PIK3C2G a role for this protein in disease. Another RNA-binding protein called fused in sarcoma/translocated in liposarcoma (FUS/TLS) has also been linked to FALS and SALS (Kwiatkowski et al.,2009; Vance et al.,2009). Although the association of FUS/TLS with pathological aggregates in SALS has been reported (Deng et al.,2010), this association is not as common as for TDP-43. The inheritable nature of FALS facilitates the identification of causal genes, because many FALS-linked genes, such asSOD1,TDP-43andFUS/TLS, are autosomal dominant and segregate according to Mendelian genetics within an ALS family. In an effort to identify genetic susceptibility factors associated with SALS, several genome-wide association studies (GWAS) have been performed. However, by and large these studies have failed to generate confirmed SALS-susceptibility genes (Bosco and Landers,2010). More recently, repeat expansions within the genome that are associated with different forms of ALS have been identified. Hexanucleotide repeat expansions in theC9ORF72gene were linked to familial frontotemporal lobar degeneration (FTLD)/ALS, FALS as well as to SALS (Dejesus-Hernandez et al.,2011; Renton et al.,2011), making this gene the most common factor in all of ALS. Moreover, repeat expansions in ataxin-2 (ATXN2) represent a susceptibility factor in SALS (Elden et al.,2010). Despite these advances in the genetics of SALS, the etiology remains unknown for RKI-1313 a majority of SALS cases, likely a reflection of the complex nature of SALS. In fact, SALS may arise from genetic as well as environmental and behavioral factors. Smoking, diet, excessive exercise, injury and exposure to environmental toxins have all been implicated in SALS (D’Amico.