Conditional truncation of the FUS protein in mice : a new animal model of the ALS/FTD continuum

Amyotrophic lateral sclerosis (ALS) and Frontotemporal dementia (FTLD) are now considered
as a unique clinicopathological spectrum referred to as ALS/FTLD. Cytoplasmic aggregation of the
physiologically nuclear FUS protein is a hallmark feature of a subset of ALS/FTLD. It remains
unknonwn whether the critical pathogenic event relies on a loss of FUS normal nuclear functions, a
toxic gain of function of FUS in the cytoplasm, or a combination of both.
To answer this question we have generated a conditional mouse model expressing truncated
FUS without nuclear localization signal - FusΔNLS. Our data showed that complete cytoplasmic
mislocalization of truncated FUS protein within spinal motor neurons is a major determinant of motor
neuron degeneration via toxic gain of function. A partial mislocalization of truncated FUS protein was
sufficient to trigger key features of ALS and of FTLD.These studies allowed the elucidation of
mechanisms underlying FUS role in ALS/FTLD, and will hopefully lead to development of therapies
for these devastating diseases.