Lee Ming-Hsiang, Chun Jerold
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
J Exp Neurosci. 2019 May 16;13:1179069519849669. doi: 10.1177/1179069519849669. eCollection 2019.
A first example of somatic gene recombination (SGR) within the human brain was recently reported, involving the well-known Alzheimer's disease (AD)-related gene amyloid precursor protein (). SGR was characterized by the creation of genomic complementary DNA (gencDNA) sequences that were identified in prefrontal cortical neurons from both normal and sporadic Alzheimer's disease (SAD) brains. Notably, SGR in SAD appeared to become dysregulated, producing many more numbers and forms of gencDNAs, including 11 single-nucleotide variations (SNVs) that are considered pathogenic mutations when they occur in families, yet are present mosaically among SAD neurons. gene transcription, reverse transcriptase (RT) activity, and DNA strand-breaks were shown to be three key factors required for gencDNA production. Many mechanistic details remain to be determined, particularly how gencDNAs are involved in AD initiation and progression. The possibility of reducing disease-related SGR through the use of RT inhibitors that are already FDA-approved for HIV and Hepatitis B treatment represents both a testable hypothesis for AD clinical trials and a genuine therapeutic option, where none currently exists, for AD patients.
最近报道了人类大脑中体细胞基因重组（SGR）的首个实例，涉及著名的与阿尔茨海默病（AD）相关的基因淀粉样前体蛋白（）。SGR的特征是产生了基因组互补DNA（gencDNA）序列，这些序列在正常和散发性阿尔茨海默病（SAD）大脑的前额叶皮质神经元中被鉴定出来。值得注意的是，SAD中的SGR似乎失调，产生了更多数量和形式的gencDNA，包括11个单核苷酸变异（SNV），这些变异在家族中出现时被认为是致病突变，但在SAD神经元中呈镶嵌式存在。基因转录、逆转录酶（RT）活性和DNA链断裂被证明是gencDNA产生所需的三个关键因素。许多机制细节仍有待确定，特别是gencDNA如何参与AD的起始和进展。通过使用已获美国食品药品监督管理局（FDA）批准用于治疗HIV和乙型肝炎的RT抑制剂来减少与疾病相关的SGR，这一可能性既是AD临床试验的一个可测试假设，也是为AD患者提供的一种目前不存在的真正治疗选择。
