Lale Gungordu

Highlights • Phenomics profile links ACh and GABA synaptic transmission to TDP-43 proteotoxicity • TDP-43 induces a (mal)adapted, disbalanced, and hyperreactive motor circuit • Reactivation of ACh neurons results in hypercontraction and spastic paralysis • Circuit rebalancing, rather than reactivating affected cell types, restores movement Summary Amyotrophic lateral sclerosis can be caused by abnormal accumulation of TAR DNA-binding protein 43 (TDP-43) in the cytoplasm of neurons.

Abstract Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia are caused by the abnormal accumulation of TAR DNA-binding protein 43 (TDP-43) in the cytoplasm of neurons. How TDP-43 accumulation leads to disease symptoms is not well-characterized. Here, we use a C. elegans model for TDP-43-induced toxicity to identify the biological mechanisms that lead to disease-related phenotypes. By applying deep behavioral phenotyping, we established a phenotypic fingerprint of TDP-43 worms.