TDP-43, RNA Metabolism, and ALS/FTD Pathology
NIH R01 NS063964
The TDP-43 RNA-binding protein is found in abnormal cytoplasmic inclusions in affected motor neurons in almost all ALS cases, and mutations in the TDP-43 gene (TARDBP) cause a rare form of familial ALS. ÌýMultiple lines of evidence suggest that TDP-43 pathology may result from both gain and loss of function of this protein. ÌýWe have found that overexpression of human TDP-43 in C. elegans results in abnormal motor neuron synapses (Ash et al, 2010), while deletion of tdp-1, the C. elegans ortholog of TDP-43, results in an abnormal accumulation of double-stranded RNA (Saldi et al, 2014). ÌýWe are currently testing the hypothesis that loss of TDP-43 nuclear function, as well as other ALS-inducing events, (e.g., the C9orf72 hexanucleotide expansion) are pathological at least in part because they perturb chromatin structure. ÌýWe propose that one result of this chromatin change may be increased expression of repetitive element transcripts, which we have recently demonstrated in patients with the C9orf72 mutation (Prudencio et al, 2017). ÌýAll our ALS/FTD studies have been done in collaboration with the Petrucelli lab (Mayo Clinic, Jacksonville).
Expression of human TDP-43 in C. elegans neurons interferes with normal motor neuron synapses (green. panel A) and defasiculation of the dorsal nerve cord (red, panel B). From Ash et al, 2010
siRNA knockdown of TDP-43 in human HeLa cells results in an accumualtion of dsRNA From Saldi et al, 2014.