题 目:Multi-phases of TDP-43: from Biology to Neurodegeneration
报告人: Dr. Haiyang Yu，UC San Diego
时 间: 12月31日（周四）9:00-10:00
地 点: Online (Zoom会议)
会议 ID：640 8468 0249
主持人: 齐志 研究员
Aggregation of the RNA binding protein TDP-43 (TAR DNA-binding protein 43) is a common pathological hallmark shared by several age-related neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The predominantly nuclear TDP-43 normallyundergoes Liquid-Liquid Phase Separation (LLPS), in which a homogenous solution separates in two compartments resembling oil droplets in vinegar. Cellular stress can induce cytoplasmic TDP-43 liquid droplets, which can transition to a solid state, suggesting that TDP-43 aggregation observed in neurodegeneration could be initiated by LLPS. We have identified that that TDP-43 is phase separated into complex droplets they name anisosomes when it loses ability to bind RNA through disease-causing mutation or post-translational acetylation. Anisosomes have spherical shells of TDP-43 (with properties of a liquid crystal) surrounding centers of HSP70 chaperones, whose activity maintains liquidity. Anisosomes form in neurons in vivo when proteasome activity is inhibited, converting into aggregates when ATP levels fall. By tagging TDP-43 with a 50-amino acid weakly self-associating domain (by folding into a beta-solenoid structure), TDP-43 readily de-mixes in the cytoplasm without added cellular stress. Using inducible TDP-43 de-mixing as a model, and APEX2-mediated proximity labeling technology, we identified unique RNA binding proteins that favor de-mixed TDP-43, including stress granule and P-body components, which were dysregulated in patient motor neurons.
Dr. Haiyang Yu is currently a postdoctoral fellow mentored by Dr. Don Cleveland, at UC San Diego. He obtained Ph.D. degree from Washington University in St. Louis in 2015 and B.Sc. degree from Nankai University in 2008. His research focuses on elucidating the cell biology of protein liquid-liquid phase separation and its patholobiological role in neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD).