Strategies to promote the maturation of ALS-associated SOD1 mutants:small molecules return to the fold

Luke McAlary; Justin J. Yerbury

doi:10.4103/1673-5374.255962

摘要：(Cu)IIiATSM (CuATSM) promotes the proper folding of famil-ial amyotrophic lateral sclerosis (fALS)-associated copper, zinc superoxide dismutase (SOD1): ALS is a progressive neurodegen-erative disease that affects motor neurons in the cortex and spinal cord, resulting in paralysis and ultimately death. The majority of cases are sporadic and the remainder are fALS where a subset of cases are associated with over 160, mostly missense, mutations in the SOD1 enzyme structure. Generally, these mutations impede the correct folding of SOD1 by disrupting either metal binding, disulfide formation, and/or dimerization, leading to the accumu-lation of misfolded SOD1 which can form the intracellular inclu-sions observed in patient tissue. The misfolding of SOD1 causes downstream effects such as ubiquitin proteasome dysfunction, endoplasmic reticulum stress, mitochondrial dysfunction, and cal-cium dyshomeostasis. Indeed, the thermal and chemical stability of SOD1, including fALS mutants, is significantly increased upon binding of metals and/or disulfide formation. Recently, a copper (Cu)-based small molecule called CuATSM was found to be effec-tive at treating multiple transgenic mouse models expressing hu-man SOD1-fALS protein (Soon et al., 2011; Roberts et al., 2014). It was found that CuATSM treatment increased the levels of soluble Cu-bound SOD1 whilst still prolonging disease progression and time until onset of symptoms. Although this was a great success, a gap in knowledge existed as to whether CuATSM would be an effective treatment in cases where the SOD1-fALS mutant has per-turbed or ablated Cu-binding. We recently showed that CuATSM is not effective at rescuing the toxicity associated with the expres-sion of SOD1 metal-binding-region mutants in cultured cells (Far-rawell et al., 2018). This suggests that although CuATSM has many therapeutic benefits not associated with SOD1 maturation, it may not be as effective for patients carrying SOD1-fALS metal-bind-ing-region mutations and, hence, other therapeutic options may need to be pursued in these cases.