The translational potential of next-generation sporadic mouse and human models of ALS/FTD

ABSTRACT/SUMMARY Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are now thought to lie within a shared umbrella of neurodegenerative disorders, all characterized by neuronal loss, behavioral deficits, and ultimately death with no truly effective treatments. It is now generally well recognized that TDP-43 dysfunction (both loss and gain of function) represents the major disease hallmark that is linked the onset and progression of these devastating diseases. However, modeling ALS/FTD has been particularly challenging, in part since slightly too much or too little TDP-43 is toxic to neurons. Our goal for this R61/R33 proposal is to develop and optimize a new ALS/FTD animal model that more accurately recapitulates the human disease spectrum. This model is based on the unanticipated finding that TDP-43 can undergo acetylation on its lysine residues, and that this specific post-translational modification (PTM) has a dramatic effect on TDP-43; it disengages TDP-43 from its target RNAs, promotes its aggregation, and leads to the loss of normal nuclear TDP-43 function. Based on this mechanism, we developed a new CRISPR-integrated mutant mouse line that incorporated an acetylation- mimicking substitution (KàQ) at position K145 in the endogenous mouse TARDBP locus, thereby generating TDP-43K145Q mutant mice, and we observed many striking hallmarks of disease including aggregated TDP-43, widespread transcriptomic and splicing alterations, and cognitive decline. These mice should provide the ideal platform for biomarker therapeutic development opportunities, not just for sporadic ALS/FTD, but potentially any neurodegenerative disease within the TDP-43 umbrella characterized by abnormal TDP-43 deposition. The goal of this R33/R61 proposal is to extend and optimize the readouts to demonstrate a progressive ALS/FTD-like phenotype using aged mouse cohorts (R33 phase) and subsequently externally validate our animal findings with those in human models, including postmortem ALS/FTD tissues and iPSC-derived neurons (R61 phase). The use of iPSC-derived sporadic ALS “trio” lines, in which the lysine residue of interest (K145) is targeted, should provide insight into causality of TDP-43 acetylation as a driver of sporadic ALS/FTD. This study is ideal for the R61/R33 mechanism, since it will highlight TDP-43K145Q mice and newly developed iPSC lines as next-generation sporadic ALS/FTD models that could radically transform the field and provide new platforms for therapeutic testing of drug candidates.