Mutant PFN1 causes ALS phenotypes and progressive motor neuron degeneration in mice by a gain of toxicity

Significance ALS is an incurable neurodegenerative disease caused by loss of motor neurons leading to paralysis and death. To understand the disease mechanism and develop therapeutics, mammalian models that phenocopy human disease are crucial. For more than two decades, transgenic animals expressing mutant copper zinc superoxide dismutase (SOD1) gene represented the only model that faithfully reproduced the human disease. Despite recent identification of new causal genes, construction of another mammalian model with progressive loss of motor neurons and concomitant clinical phenotypes has proven difficult. In this study, we have generated a transgenic mouse model by expressing mutant profilin 1. These mice replicate key features of human ALS and thus provide an in vivo system for study of disease mechanisms and development of therapeutics.