Kodavati Manohar, Hegde Muralidhar L
Department of Neurosurgery, Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX, USA.
Department of Neurosurgery, Weill Medical College, New York, NY, USA.
Neurosci Insights. 2024 Dec 14;19:26331055241305151. doi: 10.1177/26331055241305151. eCollection 2024.
Mitochondrial dysfunction plays a pivotal role in the progression of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's, and Parkinson's disease. Recent discoveries have highlighted the involvement of DNA damage and repair processes, particularly mitochondrial DNA (mtDNA) damage, in these conditions. This commentary reflects on our recent findings, demonstrating the RNA/DNA binding protein fused in sarcoma (FUS)'s crucial role in maintaining mtDNA integrity through interactions with mitochondrial DNA ligase IIIα (mtLig3). Our studies provide direct evidence of increased mtDNA damage in ALS-linked FUS mutant cells, emphasizing the potential of targeting DNA repair pathways to mitigate neurodegeneration. Furthermore, the restoration of mitochondrial function through targeted expression of human DNA ligase 1 (Lig1) in FUS mutant models showcases the therapeutic promise of DNA repair mechanisms in neurodegenerative diseases. These insights offer new molecular understanding and open up future avenues for therapeutic interventions, particularly in FUS-associated ALS and related disorders.
线粒体功能障碍在神经退行性疾病如肌萎缩侧索硬化症（ALS）、阿尔茨海默病和帕金森病的进展中起关键作用。最近的发现突出了DNA损伤和修复过程，特别是线粒体DNA（mtDNA）损伤，在这些疾病中的作用。这篇评论反思了我们最近的发现，证明了RNA/DNA结合蛋白肉瘤融合蛋白（FUS）通过与线粒体DNA连接酶IIIα（mtLig3）相互作用在维持mtDNA完整性方面的关键作用。我们的研究提供了直接证据，表明与ALS相关的FUS突变细胞中mtDNA损伤增加，强调了靶向DNA修复途径以减轻神经退行性变的潜力。此外，通过在FUS突变模型中靶向表达人类DNA连接酶1（Lig1）来恢复线粒体功能，展示了DNA修复机制在神经退行性疾病中的治疗前景。这些见解提供了新的分子理解，并为治疗干预开辟了未来的途径，特别是在与FUS相关的ALS和相关疾病中。
