Project Grant RF1NS149974

The National Institute of Neurological Disorders and Stroke awarded the University of Arizona $1,764,771 on September 1, 2026, under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853) to investigate the pathological relevance of TDP-43 interactions with translation machinery in neurodegeneration.

The award funds research into TDP-43 proteinopathy, which is characterized by mislocalization of tar DNA-binding protein 43 from the nucleus to the cytoplasm, where it forms hyperphosphorylated inclusions that disrupt RNA metabolism, mitochondrial function, and protein homeostasis in neurodegenerative diseases including amyotrophic lateral sclerosis, frontotemporal dementia, and Alzheimer's disease. The research identifies and characterizes a translation-related protein-binding motif within TDP-43 that mediates interactions with ribosomal and translation factors. Preliminary studies in mice with deletion of this motif demonstrate age-dependent accumulation of phosphorylated TDP-43 inclusions, microglial activation, neuronal loss, and progressive motor and cognitive impairments; complementary studies in iPSC-derived human neurons show impaired neuronal activity despite preserved nuclear localization and splicing function. No therapeutic strategies specifically targeting TDP-43 toxicity have reached clinical application, highlighting the urgency of understanding the mechanisms of TDP-43 aggregation initiation and sustainment.

Performance occurs in Arizona. The period of performance runs from September 1, 2026, through August 31, 2029.