Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS -associated amyotrophic lateral sclerosis

AbstractMotor neuron-extrinsic mechanisms have been shown to participate in the pathogenesis of ALS-SOD1, one familial form of amyotrophic lateral sclerosis (ALS). It remains unclear whether such mechanisms contribute to other familial forms, such as TDP-43 and FUS-associated ALS. Here, we characterize a single-copy mouse model of ALS-FUS that conditionally expresses a disease-relevant truncating FUS mutant from the endogenous murineFus gene. We show that these mice, but not mice heterozygous for aFus null allele, develop similar pathology as ALS-FUS patients and a mild motor neuron phenotype. Most importantly, CRE-mediated rescue of theFus mutation within motor neurons prevented degeneration of motor neuron cell bodies, but only delayed appearance of motor symptoms. Indeed, we observed downregulation of multiple myelin-related genes, and increased numbers of oligodendrocytes in the spinal cord supporting their contribution to behavioral deficits. In all, we show that mutant FUS triggers toxic events in both motor neurons and neighboring cells to elicit motor neuron disease.

Source: Acta Neuropathologica - February 27, 2017 Category: Neurology Source Type: research