RNA-Based Modulation of TDP-43 Mislocalization in ALS/FTD with Uridine Analogs
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, for which there are still no effective treatments to stop the disease progression. Despite considerable heterogeneity, over 97% of ALS patients show disruption of a single protein, TDP-43, which is widely linked to disease pathogenesis and known to be mutated in a small subset of ALS patients with inherited disease. TDP-43 is normally primarily located within the nucleus of the cell, a major hub for RNA processing. In ALS, for reasons that are unknown, TDP-43 leaves the nucleus and accumulates within the cytoplasmic compartment. During recent studies investigating the regulation of TDP-43 nuclear/cytoplasmic shuttling, we unexpectedly identified an intervention, based on a modified RNA base, that strongly promotes TDP-43 nuclear retention. This finding may open up a novel therapeutic approach to attenuate TDP-43 mislocalization in ALS. We now seek to understand the specific mechanism by which this strategy modulates TDP-43 localization and explore a library of related structures, to try to improve TDP-43 specificity, potency, and tolerability, and further assess the potential of this strategy as a therapeutic approach. Along the way, we hope to also identify additional cellular targets within the pathway regulating TDP-43 localization, that may be amenable to development of TDP-43-targeted therapies in ALS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211042
Entities
People
- Lindsey Hayes
Organizations
- Johns Hopkins University
- United States Army