Nuclear inclusions in CAG repeat diseases: toxic or protective?

Abstract

A variety of neurodegenerative disorders, including Huntington's disease (HD) and spinocerebellar ataxia type 1 (SCA1), are caused by the expansion of CAG repeats in the coding regions of the genes involved, giving rise to polyglutamine tracts in their mutant protein products (huntingtin and ataxin-1, respectively). The lack of homology (outside the CAG repeats) of the genes mutated in these disorders, the dominant nature of their inheritance, and the finding that mice with the relevant genes knocked out have no clinical symptoms have led to the conclusion that the expanded polyglutamine tract is a pathogenic gain-of-function mutation. The presence of nuclear inclusion bodies containing polyglutamine protein aggregates, both in patients with CAG repeat disorders and in mouse models of these diseases, suggested that these protein aggregates were toxic and therefore pathogenic. Two recent publications challenge this hypothesis.Klement and colleagues1xAtaxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice. Klement, I.A. et al. Cell. 1998; 95: 41–53Abstract | Full Text | Full Text PDF | PubMed | Scopus (800)See all References have established transgenic mice that express a mutated form of ataxin-1 in which the self-association region of the protein is deleted. This region is essential for the formation of ataxin-1 aggregates, and the transgenic mice fail to form inclusion bodies. Surprisingly, the mice develop ataxia and Purkinje cell pathology similar to that of SCA1 mice whose ataxin-1 self-association region is intact, suggesting that nuclear aggregation of ataxin-1 is not required to initiate pathogenesis in transgenic mice. These authors also investigated the role of ataxin-1 subcellular localization in SCA1 pathogenesis. Normal ataxin-1 is nuclear, but the nuclear localization signal can be abolished by substituting Lys772 for Thr. In transgenic mice carrying this mutation, ataxin-1 is cytoplasmic; the mice show no Purkinje cell pathology and do not develop any clinical symptoms of the disease.Further evidence that localization to the nucleus of expanded repeat-containing proteins is required for neurodegeneration is provided by Saudou et al.2xHuntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. 2 Saudou, F. et al. Cell. 1998; 95: 55–66Abstract | Full Text | Full Text PDF | PubMed | Scopus (1217)See all References They have found that in cultured striatal neurons, in which mutant huntingtin induces apoptosis, compounds that block nuclear localization of huntingtin suppress its ability to form intranuclear inclusions and to cause cell death. Experiments in the same culture system suggest that intranuclear inclusions are not required for neurodegeneration. In fact, suppressing inclusion formation increases death induced by mutant huntingtin in the cultured neurons, suggesting that inclusion formation might actually protect the cell from the toxic effects of expanded-repeat-containing proteins.These findings are another step in the elucidation of the mechanisms by which the polyglutamine expansions cause pathogenesis, and give us more tools to aid in the search for molecular targets that can be used for therapeutic strategies to treat these devastating conditions.