Neuronal hyperexcitability drives TDP43 pathology by upregulating shortened TDP43 protein isoforms

Abstract

Cortical hyperexcitability and mislocalization of the RNA-binding protein TDP43 are highly-conserved features in amyotrophic lateral sclerosis (ALS). Nevertheless, the relationship between these phenomena remains poorly defined. Here, we show that hyperexcitability recapitulates TDP43 pathology by upregulating shortened (s) TDP43 splice isoforms. These truncated isoforms accumulate in the cytosol, where they form insoluble inclusions that sequester full-length TDP43 via preserved N-terminal interactions. Consistent with these findings, sTDP43 overexpression is toxic to mammalian neurons, suggesting that neurodegeneration results from complementary gain- and loss-of-function mechanisms. In humans and mice, sTDP43 transcripts are enriched in vulnerable motor neurons, and we observed a striking accumulation of sTDP43 within neurons and glia of ALS patients. These studies uncover a hitherto unknown role of alternative TDP43 isoforms in ALS, and indicate that sTDP43 production may be a key contributor to the susceptibility of motor neurons in ALS.

TDP43, ALS, hyperexcitability, alternative splicing, TDP43 pathology, iPSC, iNeuron