DEFECTIVE AXONAL-TRANSPORT IN A TRANSGENIC MOUSE MODEL OF AMYOTROPHIC-LATERAL-SCLEROSIS

AMYOTROPHIC lateral sclerosis (ALS) is a degenerative disease of motor neurons, characterized by depositions of neurofilaments in the perika rya and proximal axons. The pathogenesis of ALS remains poorly underst ood, but two lines of evidence suggest that neurofilament accumulation may play a causal role. First, transgenic mice that overexpress neuro filament proteins show motor neuron degeneration(1-3) and, second, var iant alleles of the neurofilament heavy-subunit gene (NF-H) have been found in some human ALS patients(4). To investigate hom disorganized n eurofilaments might cause neurodegeneration, we examined axonal transp ort of newly synthesized proteins in mice that overexpress the human N F-H gene(1). We observed dramatic defects of axonal transport, not onl y of neurofilament proteins but also of other proteins, including tubu lin and actin. Ultrastructural analysis revealed a paucity of cytoskel etal elements, smooth endoplasmic reticulum and especially mitochondri a in the degenerating axons, We therefore propose that the neurofilame nt accumulations observed in these mice cause axonal degeneration by i mpeding the transport of components required for axonal maintenance, a nd that a similar mechanism may account for the pathogenesis of ALS in human patients.