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American Society for Experimental Neurotherapeutics Abstracts
August 2001

Genomic Neurology

Arch Neurol. 2001;58(8):1313-1314. doi:

The International Human Genome Consortium led by the National Institutes of Health (NIH) and Celera, Inc, have both announced completion of the sequencing of the human genome by the end of 2000. The identification of about 30 000 genes will be completed, allowing for the first time a detailed insight into the totality of gene expression in the nervous system. Gene regulatory functions in single cells and within cassettes of multiple neurons constituting an information circuit will be able to be studied and clarified. Elucidation of a brain code or codes for neural informatics will become possible for the first time. The Drosophila genome has already been sequenced and 13 601 genes have been identified. Of 289 human disease genes examined, the fly has orthologs to 177 genes, including genes for presenilin 1, amyloid precursor protein, tau, superoxide dismutase 1, frataxin, and dystrophin, among many others, and thus comparative genomics of fly and human provides the basis and foundation for rapid analysis of some of the basic processes involved in human disease. The current approaches for understanding neurologic disease include transgenics with mouse and fly. Gene therapy with viral vectors is under intense scientific investigation to possibly treat neurologic disease. Mouse and fly transgenics for Alzheimer, Huntington, and Machado-Joseph diseases will be reviewed and molecular therapies discussed. Immunization of mouse transgenics having a human Alzheimer disease causal gene (amyloid precursor protein 717 codon mutation) with Aβ42 clears the amyloid burden. Inhibition of gene expression of the Huntington gene with expanded CAG repeats prevents the neuropathology of Huntington disease in mouse transgenics. Induction of Hsp70 heat shock gene expression inhibits neuronal degeneration due to the Machado-Joseph disease gene with expanded CAG repeats in the fly transgenic. These molecular models will be the basis for further advances when the structure of the human genome is finally deciphered. Glia-derived nerve growth factor enhancement by an adenovirus vector to dopaminergic neurons protects them from toxic degeneration in vivo in a mouse model and is an example of the future potential for gene therapy for Parkinson disease. Gene therapy to improve neurologic function, including intellectual abilities, as shown by transgenics given a slow subunit of the N-methyl-D-aspartate receptor allowing increased ion conductance in the "smart mouse," indicates that major genetic engineering events are before us that can alter human behavior, potentially for the better. Genomics and its clinical applications can provide humankind with longer, healthier, and more productive lives, if we proceed carefully and mindfully of the difficult ethical issues facing us.