Ectopically Expressed CAG Repeats Cause Intranuclear Inclusions and a Progressive Late Onset Neurological Phenotype in the Mouse

Abstract

The mutations responsible for several human neurodegenerative disorders are expansions of translated CAG repeats beyond a normal size range. To address the role of repeat context, we have introduced a 146-unit CAG repeat into the mouse hypoxanthine phosphoribosyltransferase gene (Hprt). Mutant mice express a form of the HPRT protein that contains a long polyglutamine repeat. These mice develop a phenotype similar to the human translated CAG repeat disorders. Repeat containing mice show a late onset neurological phenotype that progresses to premature death. Neuronal intranuclear inclusions are present in affected mice. Our results show that CAG repeats do not need to be located within one of the classic repeat disorder genes to have a neurotoxic effect.

Aggregation of huntingtin in yeast varies with the length of the polyglutamine expansion and the expression of chaperone proteins

“…Overwhelming evidence indicates that the misfolding of proteins that contain polyQ expansions, but are otherwise unrelated, is a central element in the pathology of each disease. The polyQ expansion is the common determinative factor in their misfolding (39). By extension, then, our studies in yeast hold promise for investigating the mechanisms underlying all of these pathologies.…”

"In vivo" toxicity of a truncated version of the Drosophila Rst-IrreC protein is dependent on the presence of a glutamine-rich region in its intracellular domain

“…The pathogenic effect of these expanded glutamine repeats is independent of the polypeptide in which it is present since the ''in vitro'' insertion of CAG repeats in nondisease protein can also induce neurodegeneration ''in vivo'' (Ordway et al 1997). Also, the susceptibility of Drosophila to glutamine repeat disease has been demonstrated, very elegantly, by two studies: in one of them (Warrick et al 1998) the expression, in the compound eye, of the carboxy-terminal fragment of ataxin-3 containing 27 glutamines (the wildtype number) plus the 43 downstream amino acids does not seem to cause any deleterious effect, while the expression of the same construct but with a 78 amino acid long expanded glutamine repeat present in patients with Machado-Joseph Disease shows late-onset progressive cell degeneration, with neurons being particularly sensitive.…”

Of mice and men: solving the molecular mysteries of Huntington's disease

“…The factors that influence the vulnerability of different subpopulations of neurons in the various human polyglutamine-associated diseases are still not known. It has been demonstrated that if a long polyglutamine tract is engineered into a protein that normally lacks such a domain, the resulting mice display symptoms and neuropathology (including NIIs) reminiscent of the R6\2 mice (Ordway et al 1997). Each human polyglutamine-associated disease shows a distinctive pattern of neurodegeneration yet the different mutant genes have very similar expression profiles in the body.…”