Wang Fangyuan, Jing Zhou, Wang Qingyi, Li Minghe, Lu Bingqi, Huo Ao, Zhao Chenglin, Zhou Huanyu, Liang Wulong, Hu Weihua, Fu Xudong
Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.
Department of Clinical Medicine, The First Clinical Medical College of Zhengzhou University, Zhengzhou University, Zhengzhou, China.
Brain Behav. 2025 Jan;15(1):e70283. doi: 10.1002/brb3.70283.
Neurodegenerative diseases involve progressive neuronal dysfunction and cognitive decline, posing substantial global challenges. Although the precise causes remain unclear, several studies highlight the role of protein metabolism abnormalities in disease development. This study investigates the causal links between variations in mitochondrial protein genes and neurodegenerative diseases, aiming to elucidate their potential contributions to disease progression and identify novel therapeutic strategies.
Herein, we utilized data from genome-wide association studies (GWAS) on mitochondrial proteins and neurodegenerative diseases. Bidirectional Mendelian randomization (MR), employing instrumental variables (IVs), was used to assess causal relationships. The primary method for estimating causal effects was the inverse variance-weighted (IVW) method, supplemented by additional MR approaches.
Bidirectional MR revealed significant associations between mitochondrial protein gene variants and neurodegenerative diseases. Specifically, associations were found with Alzheimer's disease (AD) (three proteins), Parkinson's disease (PD) (four proteins), amyotrophic lateral sclerosis (ALS) (six proteins), multiple sclerosis (two proteins), and dementia with Lewy bodies (four proteins). Conversely, analyses indicated significant associations of neurodegenerative diseases with mitochondrial protein gene variants, notably with AD, dementia with Lewy bodies, and multiple sclerosis, affecting multiple mitochondrial protein levels. Bidirectional causality was observed between dementia with Lewy bodies and C21orf33.
Using MR, we identified significant links between mitochondrial protein gene mutations and the risk of neurodegenerative diseases. These results highlight reciprocal relationships where certain neurodegenerative diseases influence mitochondrial protein expression levels. These findings underscore the pivotal role of mitochondrial proteins in neurodegenerative diseases, offering critical insights into disease mechanisms and potential therapeutic avenues.
神经退行性疾病涉及神经元功能的进行性衰退和认知能力下降，给全球带来了重大挑战。尽管确切病因尚不清楚，但多项研究强调了蛋白质代谢异常在疾病发展中的作用。本研究调查线粒体蛋白质基因变异与神经退行性疾病之间的因果关系，旨在阐明它们对疾病进展的潜在影响，并确定新的治疗策略。
在此，我们利用了关于线粒体蛋白质和神经退行性疾病的全基因组关联研究（GWAS）数据。采用双向孟德尔随机化（MR），利用工具变量（IVs）来评估因果关系。估计因果效应的主要方法是逆方差加权（IVW）法，并辅以其他MR方法。
双向MR揭示了线粒体蛋白质基因变异与神经退行性疾病之间的显著关联。具体而言，发现与阿尔茨海默病（AD）（三种蛋白质）、帕金森病（PD）（四种蛋白质）、肌萎缩侧索硬化症（ALS）（六种蛋白质）、多发性硬化症（两种蛋白质）和路易体痴呆（四种蛋白质）有关。相反，分析表明神经退行性疾病与线粒体蛋白质基因变异存在显著关联，特别是与AD、路易体痴呆和多发性硬化症有关，影响多种线粒体蛋白质水平。在路易体痴呆和C21orf33之间观察到双向因果关系。
通过MR，我们确定了线粒体蛋白质基因突变与神经退行性疾病风险之间的显著联系。这些结果突出了某些神经退行性疾病影响线粒体蛋白质表达水平的相互关系。这些发现强调了线粒体蛋白质在神经退行性疾病中的关键作用，为疾病机制和潜在治疗途径提供了重要见解。
