Significance Mutations in the RNA binding protein TDP-43 cause amyotrophic lateral sclerosis and frontotemporal dementia. Through expressing disease-causing mutants in mice and genome-wide RNA splicing analyses, mutant TDP-43 is shown to retain normal or enhanced activity for facilitating splicing of some RNA targets, but “loss-of-function” for others. These splicing changes, as well as age-dependent, mutant-dependent lower motor neuron disease, occur without loss of nuclear TDP-43 or accumulation of insoluble aggregates of TDP-43.

ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43