This grant proposal is based on recent discoveries that motor neuron degeneration in transgenic mice bearing a neurofilament (NF) transgene results from expression of NE mRNA -not NE protein by the transgene. The findings have led to the working hypothesis that the neuropathic effects of NF transgenes are due to regulatory factors that bind to NF mRNA and control the level of NF gene expression. We believe that the regulatory factors also mediate post-transcriptional processing and expression of other neuronal gene products, including gene products whose expressions are necessary In maintain the homeostasis of motor neurons. Expression of a NF transgene may therefore give rise to a neurodegenerative state by altering the composition of regulatory factors and decreasing expression of gene products that are essential for motor neuron viability. The proposed studies will identify and clone the regulatory factors that bind to NF mRNA and mediate the neuropathic effects of NF transgenes. Specific RNA-protein interactions will be used to identify and clone (I) the regulatory factors that ~iac~ to the neuropathic elements in NF mRNA as well as (2) neuronal mRNAs that bind to the regulatory factors and have a potential role in altering neuronal homeostasis. The studies involve pathogenetic mechanisms causing motor neuron degeneration and have far-reaching implications about the diagnosis, treatment and cure of motor neuron diseases.
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