NEUROFILAMENTS, SOD1 AND MOTOR NEURON DISEASE

University Of California San Diego, La Jolla CA

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Abstract

DESCRIPTION: This application is aimed at elucidating the fundamental role of neurofilament subunits (NF-L, NF-M, NF-H) in specifying the axonal volume of neural cells and their role in motor neuron disease. Aim 1 will continue the investigation of the mechanism of neurofilament dependent growth using transgenic mice that over express or are deleted for each subunit. In particular the role played by the phosphorylated tail domains of NF-M and NF-H in specifying the three dimensional array of neurofilaments and how they are linked to other axonal components will be examined. Aim 2 will study the mechanism of neurofilament- dependent motor neuron disease, expanding previous observations that increased neurofilament burden in axons or expression of a mutant NF-L subunit cause selective motor neuron failure in transgenic mice. Point mutations in superoxide dismutase 1 (SOD1) which cause amyotrophic lateral sclerosis (ALS) in human also cause motor neuron disease in transgenic mice and Aim 3 will investigate the mechanism by which defects in this ubiquitously expressed cytoplasmic protein lead to the selective death of motor neurons. Experiments will test directly whether the toxic properties of SOD1 mutations arise through an effect on neurofilament accumulation and transport.