Section on DNA Repair, National Institute on Aging, Baltimore, MD 21224, USA.
Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, 11527, Greece.
Nucleic Acids Res. 2024 Oct 14;52(18):10965-10985. doi: 10.1093/nar/gkae705.
Alzheimer's disease (AD) is a neurodegenerative disorder representing a major burden on families and society. Some of the main pathological hallmarks of AD are the accumulation of amyloid plaques (Aβ) and tau neurofibrillary tangles. However, it is still unclear how Aβ and tau aggregates promote specific phenotypic outcomes and lead to excessive oxidative DNA damage, neuronal cell death and eventually to loss of memory. Here we utilized a Caenorhabditis elegans (C. elegans) model of human tauopathy to investigate the role of DNA glycosylases in disease development and progression. Transgenic nematodes expressing a pro-aggregate form of tau displayed altered mitochondrial content, decreased lifespan, and cognitive dysfunction. Genetic ablation of either of the two DNA glycosylases found in C. elegans, NTH-1 and UNG-1, improved mitochondrial function, lifespan, and memory impairment. NTH-1 depletion resulted in a dramatic increase of differentially expressed genes, which was not apparent in UNG-1 deficient nematodes. Our findings clearly show that in addition to its enzymatic activity, NTH-1 has non-canonical functions highlighting its modulation as a potential therapeutic intervention to tackle tau-mediated pathology.
阿尔茨海默病（AD）是一种神经退行性疾病，给家庭和社会带来了重大负担。AD 的一些主要病理特征是淀粉样斑块（Aβ）和 tau 神经原纤维缠结的积累。然而，目前仍不清楚 Aβ和 tau 聚集如何促进特定的表型结果，并导致过度的氧化 DNA 损伤、神经元细胞死亡，最终导致记忆丧失。在这里，我们利用人类 tau 病的秀丽隐杆线虫（C. elegans）模型来研究 DNA 糖苷酶在疾病发展和进展中的作用。表达聚集形式 tau 的转基因线虫表现出线粒体含量改变、寿命缩短和认知功能障碍。在秀丽隐杆线虫中发现的两种 DNA 糖苷酶（NTH-1 和 UNG-1）中的任何一种的遗传缺失都改善了线粒体功能、寿命和记忆障碍。NTH-1 的消耗导致差异表达基因的显著增加，而在 UNG-1 缺陷线虫中则不明显。我们的研究结果清楚地表明，除了其酶活性外，NTH-1 还具有非经典功能，强调了其作为治疗 tau 介导的病理学的潜在治疗干预的调节作用。
