中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2019, Vol. 14 ›› Issue (9): 1511-1512.doi: 10.4103/1673-5374.255962

• 观点:退行性病与再生 • 上一篇    下一篇

促进肌萎缩侧索硬化症相关超氧化物歧化酶突变体成熟的策略：小分子正常折叠

  

  • 出版日期:2019-09-15 发布日期:2019-09-15

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

Luke McAlary 1, 2, Justin J. Yerbury 1, 2   

  1. 1 Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia;
    2 School of Chemistry and Molecular Bioscience, Molecular Horizons, Faculty of Science, Medicine and Health, University of Wollongong, NSW, Australia
  • Online:2019-09-15 Published:2019-09-15
  • Contact: Justin J. Yerbury, PhD, jyerbury@uow.edu.au.

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摘要：

orcid: 0000-0003-2528-7039 (Justin J. Yerbury)

Abstract:

(Cu) II ATSM (CuATSM) promotes the proper folding of familial amyotrophic lateral sclerosis (fALS)-associated copper, zinc superoxide dismutase (SOD1): ALS is a progressive neurodegenerative 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 accumulation of misfolded SOD1 which can form the intracellular inclusions observed in patient tissue. The misfolding of SOD1 causes downstream effects such as ubiquitin proteasome dysfunction, endoplasmic reticulum stress, mitochondrial dysfunction, and calcium 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 effective at treating multiple transgenic mouse models expressing human SOD1-fALS protein. 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 perturbed or ablated Cu-binding. We recently showed that CuATSM is not effective at rescuing the toxicity associated with the expression of SOD1 metal-binding-region mutants in cultured cells. 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-binding-region mutations and, hence, other therapeutic options may need to be pursued in these cases.