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.