Investigation of an amyotrophic lateral sclerosis-associated profilin 1 mutant

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating disease that has no cure. Mutations in profilin 1 were identified as a cause of familial ALS in 2012. We investigated the impact of expressing mutant profilin 1 in cultured primary neurons and in spinal cords during mouse development. Our data from studies using transfected primary hippocampal mouse neurons show that profilin 1 C71G expression results in increased dendritic spine density. These results show that expression of profilin 1 C71G alters cell morphology. We developed a novel mouse model with expression of PFN1 C71G targeted to α-motor neurons in the spinal cord during development. Adult mice had no transgene expression. When the embryos of these mice were analysed, they showed evidence of reduced neuronal outgrowth and abnormal brain development. Adult mice had no transgene expression. These mice presented with motor deficits and a reduction in the number of motor neurons in the spinal cord. Further analysis of these motor neurons in these mice revealed reduced levels of TDP and ChAT. Although profilin 1 C71G was only expressed during development, adult mice presented with some ALS-associated pathology and motor symptoms. This study highlights the effect of profilin 1 during neurodevelopment and the impact that this may have in amyotrophic lateral sclerosis