中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2021, Vol. 16 ›› Issue (1): 104-105.doi: 10.4103/1673-5374.286960

• 观点:神经损伤修复保护与再生 • 上一篇    下一篇

修复肌萎缩性侧索硬化症断裂：运动神经元变性中的DNA损伤和修复

  

  • 出版日期:2021-01-15 发布日期:2020-11-25

Mending the broken in amyotrophic lateral sclerosis: DNA damage and repair in motor neuron degeneration

Byung Woo Kim, Lee J. Martin*   

  1. Department of Pathology, Division of Neuropathology, the Pathobiology Graduate Training Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA (Kim BW, Martin LJ)
    Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA (Martin LJ)
  • Online:2021-01-15 Published:2020-11-25
  • Contact: Lee J. Martin, PhD, martinl@jhmi.edu.
  • Supported by:
    This work was supported by grants from the U.S. Public Health Service, NIH-NINDS (NS034100, NS065895, NS052098, NS079348) and NIH-NIA (AG016282). 

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摘要： https://orcid.org/0000-0001-8961-7020 (Lee J. Martin) 

Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes paralysis and respiratory failure (Petrov et al., 2017). The driving mechanisms are unknown, and there are no effective treatments (Petrov et al., 2017). Aging and a few gene mutations, a common one being missense mutations in superoxide dismutase-1 (SOD1), are risk factors for ALS (Figure 1). The recent Food and Drug Administration approval of edaravone for the treatment of ALS putatively supports a role for oxidative and nitrative stresses in the disease processes (Figure 1A). DNA damage, abnormalities in DNA repair, and other nuclear abnormalities are implicated also in the pathogenesis of human ALS (Bradley and Krasin, 1982; Kim et al., 2020). DNA damage as an upstream pathogenic event in human ALS is supported by evidence for p53 activation and its import into the nucleus of motor neurons (Martin, 2000), and hyperactivation and nuclear accumulation of apurinic/apyrimidinic endodeoxyribonuclease-1 (Shaikh and Martin, 2002). Kim et al. (2020) discovered that upper and lower motor neurons in postmortem central nervous system (CNS) from ALS patients, mostly sporadic ALS in comparison to age-matched controls, accumulate several different types of DNA lesions and engage a prominent DNA damage response (DDR), as evidenced by accumulation of nuclear Abelson non-receptor tyrosine kinase and breast cancer type 1 susceptibility protein, and the serine/threonine protein kinase ataxia telangiectasia mutated activation (Figure 1A). Apyriminidinic sites, single-stranded DNA, oxidized DNA, and DDR proteins are present in motor neurons at pre-attritional stages and throughout the somatodendritic attritional stages of neurodegeneration (Kim et al., 2020). Motor neurons with DNA damage are also positive for activated p53 and cleaved caspase-3 (Figure 1A). These recent findings support the concept that, in human ALS, the motor neuron degeneration is a cell-autonomous form of programmed cell death (Martin, 1999).