RNA结合蛋白TDP-43参与RNA代谢与加工的多个过程，它的几十种突变与一系列常见并致命的神经退行性疾病密切相关，且病理组织中存在TDP-43阳性的异常蛋白聚集，这些疾病统称为TDP-43蛋白病，严重影响神经系统的正常功能，危害我国中壮及老年人群的健康。我们的前期研究发现，使用免疫电镜检测TDP-43蛋白病患者脑样本，含有TDP-43纤维沉淀的神经细胞出现严重的线粒体损伤。本项目利用细胞系和原代神经元转染，在细胞水平分析表达TDP-43突变体对线粒体形态、功能及能量代谢的影响，筛选与TDP-43相互作用的线粒体蛋白质；利用已建立的TDP-43转基因果蝇模型，在动物水平上确定介导TDP-43线粒体定位的蛋白质，研究其功能及它们相互作用引起线粒体损伤的机制；利用改进的微流控芯片高通量筛选挽救神经元轴突线粒体损伤的小分子药物，为预防和缓解TDP-43异常表达导致多种神经退行性病变提供理论依据。

TAR-DNA binding protein 43 (TDP-43), encoding a multi-functional DNA/RNA binding protein, plays an important role in RNA metabolism, from transcriptional to posttranscriptional gene regulation. Recent studies have discovered mutations in the human TDP-43 gene among patients with TDP-43 proteinopathy. This group of common and fatal neurodegenerative diseases includes motor neuron diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), the second common form of early-onset dementia after Alzheimer’s diseases (AD). ALS and FTLD can cause movement defects and cognitive impairments, representing a huge socio-economical burden for countries including China. In our pilot study, immuno-electronic microscopy (immuno-EM) analyses of FTLP-TDP patient brain samples reveal that TDP-43 positive fibril-containing neurons exhibit severe mitochondrial damage. In this project, we propose to use multi-disciplinary approaches to study the role of TDP-43 in pathogenesis of TDP-43 proteinopathy. Using cell lines and primary neuron culture, we plan to systematically examine effects of wild-type and disease-mutant TDP-43 on morphology and function of mitochondria, as well as identify mitochondrial proteins interacting with TDP-43. With our established TDP-43 transgenic fly model, we then confirm the protein candidate(s) mediating TDP-43 mitochondrial translocation and dissect molecular and cellular mechanisms of TDP-43 induced mitochondrial damage. Finally, we are going to screen small molecular compounds using our modified microfluidic chamber to identify drugs rescuing TDP-43 induced mitochondrial damage. This study will provide new insights into common pathogenic mechanisms underlying a range of neurodegenerative diseases associated with TDP-43 and information useful for future development of diagnostic and therapeutic tools for this group of devastating diseases.