Neurofilaments, SOD1 and Motor Neuron Diseases

Ludwig Institute For Cancer Research, Melbourne

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Abstract

DESCRIPTION: Motor and sensory neurons of the periphery are among the largest cells, with volumes up to 5,000 times that typical for animal cells. Most of this volume is acquired just after stable synapse formation and concomitant with myelination, during which time the axons grow in diameter by more than an order of magnitude. One basic cell biological question is how is this volume expansion, a key component for conduction velocity, is mediated. Earlier efforts using classical and molecular genetics have demonstrated that incorporation into axons of an ordered array of neurofilaments is essential for radial growth. Using gene targeting and gene replacement, the principles through which neurofilaments structure axoplasm to support axonal volume will be determined. This will include a focus on identification of the interfilament crosslinkers that probably support growth through formation a deformable, three dimensional, space filling, structural array. Beyond this, multiple preceding lines of evidence, including use of transgenic mice expressing mutated neurofilament genes, has demonstrated that disorganization/damage to neurofilaments can itself provoke death of motor neurons that mimics most aspects of the most abundant human adult motor neuron disease, amyotrophic lateral sclerosis (ALS). With neurofilamentous pathology frequently reported in human ALS, a search will be undertaken for possible neurofilament mutations or variants as causes or contributors to human ALS. A parallel approach will search for covalent damage to neurofilaments and their associated components that may develop during ALS. A high through put screen will be conducted for agents that can provoke disassembly of neurofilaments. Lastly, for human ALS, a proportion of dominantly inherited disease arises from mutation in superoxide dismutase (SOD 1), but the mechanism through which mutation in this ubiquitously expressed protein provokes late onset, selective motor neuron killing has remained elusive. To this, transgenic mice that develop disease from expressing any of three SOD 1 mutants, as well as cell cultures from those mice, will be used to test how toxicity of the mutants is related to binding of the catalytic copper or zinc, whether toxicity is cell autonomous (that is, arises uniquely from damage directly within motor neurons) and how aggregation of mutant SOD 1, and compromise in protein folding and catabolism, contributes to toxicity.