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Lindsey Hayes, PhD
Associate Professor, Department of Neurobiology, Johns Hopkins University School of Medicine
RNA-based regulation of TDP-43 localization and function
Host: Dr. Haining Zhu
Disruption of the essential nucleic-acid binding protein TDP-43 is widely observed in age-related neurodegenerative diseases such as ALS and FTD, where TDP-43 mislocalization, aggregation and loss of function have been shown to drive neurodegeneration. TDP-43 binds up to one-third of the transcriptome at GU-rich RNA motifs to regulate RNA processing and stability. In turn, RNA strongly regulatesTDP-43 localization and solubility. We recently reported that TDP-43 binding to nuclear GU-rich pre-mRNAs tethers TDP-43 within the nucleus and restricts its availability for passive diffusion through nuclear pore channels. In subsequent studies, we have found that transfection of cells with synthetic, multivalent GU-rich oligonucleotides or expression of stable, non-coding GU-rich circular RNAs promotes TDP-43 nuclear localization, through high affinity GU-RNAs also disrupt TDP-43 function and can promote cytoplasmic stress granule formation IN ongoing studies we are varying the RNA motif, expression level, and localization toward a goal of promoting TDP-43 nuclear localization and solubility without perturbing its function. These studies aim to develop novel TDP-43 regulatory RNAs and provide fundamental insights into the molecular rules governing TDP-43 homeostasis.