TDP-43 cytoplasmic mislocalization and loss of function is a hallmark of neurodegeneration in ALS and other TDP-43 proteinopathies and an important therapeutic target. In an effort to better understand potential upstream causes of TDP-43 mislocalization in disease, we investigated the mechanism and regulation of TDP-43 nuclear export, and found that TDP-43 exits the nucleus by passive diffusion. The normal predominantly nuclear localization of TDP-43 is maintained by binding to nuclear pre-mRNAs at GU-rich motifs. This model suggests that disregulation of RNA metabolism may be upstream of TDP-43 mislocalization in disease, and that RNA-based strategies may be useful to rescue TDP-43 nuclear localization and function. Candidate strategies in development will be discussed.
Friday, May 5, 2023
RNA-based regulation of TDP-43 nuclear localization
This event is part of the Neurology/Neuroscience Research Seminar.