MICE OVEREXPRESSING THE HUMAN NEUROFILAMENT HEAVY GENE AS A MODEL OF ALS

We discuss the evidence, based on the analysis of transgenic mice over expressing the human neurofilament (NF) heavy gene, that abnormal NF a ccumulations can provoke neurodegeneration of motor neurons. Transgeni c mice overexpressing by two-fold the normal levels of human NF-H prot eins develop a progressive motor neuron disease with several pathologi c features reminiscent of those found in amyotrophic lateral sclerosis (ALS). A plausible mechanism for the selective motor neuron degenerat ion is that exceeding levels of NF-H cross-linkages impede transport o f newly Synthesized NF structures. The abnormal NF accumulations in pe rikarya and proximal axons is accompanied by a disruption in axonal tr ansport of not only NF proteins but also of other components required for maintenance of axons. The relevance of the NF-H transgenics as a m odel of ALS is discussed in light of our current knowledge of motor ne uron disease.