Our laboratory has a long-standing interest in the structural, biochemical and molecular properties of neurofilament (NF) proteins. These studies are now directed at mechanisms whereby disruption of NF assembly and aggregation of the light neurofilament (NFL) protein lead to motor neuron degeneration and disease. Although accumulations of NFs in neurons-at-risk have long been regarded as a reactive or secondary event in neuronal disease, there is new and growing evidence that alterations in assembly and aggregation of NFL play a primary role in the pathogenesis of motor neuron disease. The driving force behind the new direction of study has been the discovery that mutations in NFL and in small heat shock proteins, HSPB1 and HSPB8, cause motor neuron degeneration in CMT2E, CMT2F and CMT2L forms of Charcot-Marie-Tooth (CMT) disease.
Disease-causing mutations in NFL, HSPB1 and HSPB8 are known to disrupt assembly and lead to aggregation of NFL protein. We show that expression of CMT-mutant NFL or HSPB1 directly in motor neurons disrupts NF assembly, leads to aggregation of NFL protein and causes progressive degeneration and loss of viability of motor neurons. Most importantly, we show that the neurotoxic effects are dependent on the presence of the NFL gene or gene products in motor neurons. The findings support a working hypothesis that disruption of assembly and aggregation of NFL protein are part of a pathway leading to motor neuron degeneration. The hypothesis argues that the pathogenesis of motor neuron disease is characterized by the same features as found in other major neurodegenerative diseases; namely, that abnormal protein aggregation is a triggering event in the degeneration of neurons-at-risk and that aggregation of widely expressed proteins leads to highly selective degeneration of a very small subset of neurons-at-risk in disease states.