Expanding our understanding of polyglutamine diseases through mouse models.

The above mouse models strongly support the notion that polyglutamine pathogenesis is caused by some toxic function gained by the mutant protein as a result of the expanded CAG repeat. Selective neuronal vulnerability may be determined by the protein context of the expanded polyglutamine tract and the level of protein in those cells. Mutant proteins may be abnormally processed or interact abnormally with other proteins, which presumably contribute to selective neuronal dysfunction and degeneration (Figure 1Figure 1).Figure 1Model for the Pathogenesis of Polyglutamine DiseasesView Large Image | View Hi-Res Image | Download PowerPoint SlideIs the pathogenesis of all polyglutamine disorders mediated by the same mechanism(s)? The answer is most likely “yes and no.” Protein misfolding and turnover seem to be shared features, since glutamine tract expansion leads to the accumulation of mutant protein in all the diseases evaluated. The variation in sites of accumulation of the mutant protein, however—in SCA2 and SCA6, the mutant proteins accumulate in the cytoplasm, not the nucleus (6xHuynh, D.P, Del Bigio, M.R, Ho, D.H, and Pulst, S.M. Ann. Neurol. 1999; 45: 232–241Crossref | PubMed | Scopus (114)See all References, 8xIshikawa, K, Fujigasaki, H, Saegusa, H, Ohwada, K, Fujita, T, Iwamoto, H, Komatsuzaki, Y, Toru, S, Toriyama, H, Watanabe, M et al. Hum. Mol. Genet. 1999; 8: 1185–1193Crossref | PubMed | Scopus (147)See all References)—implies that the downstream pathogenic mechanisms may differ. Polyglutamine expansion could cause the mutant proteins to adopt altered conformations, leading to their ubiquitination, aggregation, and resistance to proteasomal degradation. Over the course of the disease, the ubiquitin–proteasome system could become encumbered by the aggregate-prone proteins, which in turn could alter the turnover of other critically short-lived proteins. Although neuronal dysfunction and cytoplasmic changes could occur very early in the pathogenesis, later-stage disruptions of nuclear structures and/or functions might be common factors in several polyglutamine diseases.Even a unifying model for polyglutamine-induced neurodegeneration, however, leaves a number of questions unanswered including the following key issues. What cell-specific determinants underlie the selectivity of neuronal degeneration: cell-specific interactors or cell-specific alterations of gene expression? Are the functions gained by the mutant proteins novel or intrinsic? What are the earliest physiological changes in affected neurons? Is there therapeutic potential in inhibiting cleavage or nuclear transport of the mutant proteins?Present and future generation animal models—mouse, Drosophila, and C. elegans alike—will be invaluable tools in addressing many of these questions. For example, the significance of interacting proteins in selective neuronal vulnerability can now be studied by mating the various models with animals that either lack or overexpress the interactors in the vulnerable neurons. The emerging principle that truncation of the parent protein is an important step in the pathogenesis of several of these diseases can now be tested by investigating the posttranslational processing of these proteins in vivo. Ona et al. 1999xOna, V.O, Li, M, Vonsattel, J.P, Andrews, L.J, Khan, S.Q, Chung, W.M, Frey, A.S, Menon, A.S, Li, X.J, Stieg, P.E et al. Nature. 1999; 399: 263–267Crossref | PubMed | Scopus (496)See all ReferencesOna et al. 1999, for example, recently showed that caspase-1 is activated in the R6/2 mice, and inhibiting its activity reduces endogenous huntingtin cleavage. Furthermore, this causes several of the phenotypes described above to progress more slowly. It would be interesting to see if inhibition of caspase-1 would also modify the phenotype of mice expressing full-length huntingtin. Lessons learned from in vitro studies—e.g., ataxin-1 aggregation in transfected HeLa cells can be suppressed by overexpressing a molecular chaperone—can now be carried into mouse models to determine whether these modifications occur in vivo. Likewise, the putative involvement of the ubiquitin–proteasome pathway might be investigated by mating the polyglutamine mouse models with mice that have deficiencies in this pathway or, conversely, with transgenic mice overexpressing factors within the pathway. Most importantly, mouse models allow the study of early phenotypic changes for which patient material is seldom available. Gene chips and other array technologies should prove invaluable for finding transcriptional changes early in the disease process. Characterizing changes that occur prior to any pathological events will greatly expand our knowledge of the molecular mechanisms that cause neurodegeneration in polyglutamine diseases.*To whom correspondence should be addressed (e-mail: hzoghbi@bcm.tmc.edu).