Yoon Grace, Caldecott Keith W
Divisions of Clinical and Metabolic Genetics and Neurology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
Genome Damage and Stability Centre, University of Sussex, Brighton, United Kingdom.
Handb Clin Neurol. 2018;155:105-115. doi: 10.1016/B978-0-444-64189-2.00007-X.
Hereditary cerebellar ataxias are genetically and clinically heterogeneous, and an important subgroup of these disorders are caused by defects in DNA repair. These conditions are inherited in an autosomal-recessive fashion, with the main clinical feature being ataxia due to cerebellar degeneration. The nervous system in general, and the cerebellum in particular, is especially susceptible to DNA damage, although the underlying mechanism for this vulnerability has not been fully elucidated. Defects in DNA repair result in progressive accumulation of oxidative damage to DNA. This damage causes loss of normal neuronal function which may in turn cause defense mechanisms involved in maintaining genomic integrity to trigger programmed cell death and neuronal loss. Disorders of DNA single-strand break repair almost exclusively impact the cerebellum, highlighting the critical requirement for genomic stability in this specific tissue. One possible explanation is due to the brain's dependence on high levels of oxidative metabolism and subsequent generation of free radicals, which have the potential to cause single-strand breaks in DNA. A compounding factor is that neurons do not possess alternative DNA repair processes which are present in other tissues, and therefore may be comparatively more vulnerable to defects in the DNA single-strand break repair machinery. Both neurodevelopmental and neurodegenerative diseases arise from mutations in genes coding for proteins involved in DNA repair, underscoring the importance of this process to normal cerebellar function in children and adults.
遗传性小脑共济失调在遗传和临床方面具有异质性，这些疾病的一个重要亚组是由DNA修复缺陷引起的。这些病症以常染色体隐性方式遗传，主要临床特征是由于小脑变性导致的共济失调。一般而言，神经系统，尤其是小脑，对DNA损伤特别敏感，尽管这种易损性的潜在机制尚未完全阐明。DNA修复缺陷导致DNA氧化损伤的逐渐积累。这种损伤会导致正常神经元功能丧失，进而可能导致参与维持基因组完整性的防御机制触发程序性细胞死亡和神经元丢失。DNA单链断裂修复障碍几乎只影响小脑，突出了该特定组织中基因组稳定性的关键需求。一种可能的解释是，大脑依赖高水平的氧化代谢以及随后自由基的产生，而自由基有可能导致DNA单链断裂。一个复杂因素是，神经元不具备其他组织中存在的替代DNA修复过程，因此可能相对更容易受到DNA单链断裂修复机制缺陷的影响。神经发育疾病和神经退行性疾病均由参与DNA修复的蛋白质编码基因突变引起，这凸显了该过程对儿童和成人正常小脑功能的重要性。
