Gene Silencers and the Neurosurgeonsʼ Armamentarium

Abstract

Novel discoveries in neuroscience lend increasing evidence for the use of selective inhibition of gene expression to treat a variety of disorders that are more familiar to our neurology colleagues. In a recent publication in Nature Medicine (10:816–20, 2004) a group of researchers led by Beverly Davidson from the University of Iowa have demonstrated the successful treatment of spinocerebellar ataxia in mice through the stereotactic injection of a gene silencer. The strategy for using a gene sniper relies on the technique of interference RNA (RNAi) which has contributed greatly to our understanding of the molecular mechanisms of disease. We have previously highlighted (Neurosurgery. 54(3):N2, March 2004) the advantages of disease models for Parkinson that rely on RNAi to knockdown the expression of tyrosine hydroxlyase in the substantia nigra of young mice (Nature Medicine 9: 1539-44, 2003). In the present example, RNAi is proving its worthiness as a treatment mechanism. Xia et al. have examined spinocerebellar ataxia type 1 (SCA1), a disease that is characterized by a trinucleotide repeat that is characteristic of several neurodegenerative diseases including Huntington's. The gene mutation in SCA1 results in the aberrant expression of a protein called ataxin-1 which produces characteristic nuclear inclusions in Purkinje cells. Through a series of elegant experiments, Xia et al. show that a short hairpin RNA (shRNA) derived from a segment of the ataxin-1 gene can be transfected into Purkinje cells by an adenoassociated virus (AAV). The stereotactic injection of the AAV between lobules of the mouse cerebellum results in a dramatic improvement in the pathology and neurological function of transgenic SCA1 mice. These results suggest that it is possible to arrest the neurodegenerative process by disrupting the formation of intranuclear aggregates. It would appear that as neurosurgeons, we need to be aware of these evolving treatment strategies as their application and development will rely on our expertise. BRYAN E. FIGUEROA, M.D. ROBERT M. FRIEDLANDER, M.D., M.A. BASIC NEUROSCIENCES