Aggregation of Light Neurofilament Protein has Direct Neurotoxic Effect on Motor Neurons

Abstract

Aggregates of light neurofilament (NFL) protein are hallmark pathological features in mouse models of motor neuron disease due to expression of untranslated NFL RNA or G93A mutant SOD1 transgenes (Lin et al., Hum Mol Genet 14:, 2005). To assess whether NFL aggregation has direct neurotoxic effects on motor neurons, cultured motor neurons were microinjected with cDNAs to P8R or Q333P missense NFL, mutations which cause autosomal dominant motor and sensory neuropathy in Charcot-Marie-Tooth (CMT2E) disease and lead to disruption of assembly and aggregation of NFL in neuronal cells. CMT-mutant NFL undergoes aggregation and leads to progressive degeneration of targeted motor neurons. Aggregation as well as the toxic effect of mutant NFL can be reduced and reversed by co-injection of HSPB1, a small heat shock protein that interacts with NFL and, when mutated, causes CMT2F motor neuropathy and leads to aggregation of wild-type NFL in transfected cells. The finding support the view that aggregates of NFL protein have direct neurotoxic effects on motor neurons and represent a potential promising target for therapeutic intervention in motor neuron disease. Supported by NIH (WWS) and MDA (HL) grants.