Expanded polyglutamine in the Machado–Joseph disease protein induces cell death in vitro and in vivo

Abstract

Recently, we identified a novel gene, MJD1, which contains an expanded CAG triplet repeat in Machado-Joseph disease. Here we report the induction of apoptosis in cultured cells expressing a portion of the MJD1 gene that includes the expanded CAG repeats. Cell death occurs only when the CAG repeat is translated into polyglutamine residues, which apparently precipitate in large covalently modified forms. We also created ataxic transgenic mice by expressing the expanded polyglutamine stretch in Purkinje cells. Our results demonstrate the potential involvement of the expanded polyglutamine as the common aetiological agent for inherited neurodegenerative diseases with CAG expansions.

A neuroendocrine dysfunction, not testicular mutant ataxin-3 cleavage fragment or aggregate, causes cell death in testes of transgenic mice

“…2 Neurotoxicity is associated with a critical concentration 4 of a mutant ataxin-3 putative-cleavage fragment containing the polyglutamine expansion. 5 It is controversial whether neurotoxicity is also associated with the formation of neuronal mutant ataxin-3 aggregate and intranuclear inclusions. [3][4][5][6] Here, we used a mouse model of mutant ataxin-3 toxicity to examine whether such pathogenic markers occur in dying non-neuronal cells.…”

Unstable expansion of triplet repeats as a new disease mechanism for neurodegenerative diseases

“…It is intriguing to hypothesize that thus truncated protein product containing the polyglutamine tract is toxic to neuronal cells. As mentioned above the toxicity of expanded polyglutamine tracts to neuronal cells has recently been demonstrated in a transgenic mouse and a cell culture system using truncated MJD cDNA (Ikeda et al, 1996). Taken together, the findings described above suggest that processing of gene products with an expanded polyglutamine tract and the toxicity of the processed products of the proteins play key roles in the pathogenesis of neurodegeneration.…”

“…Recently Ikeda et al reported that COS cells transfected with truncated MJD cDNA with an expanded CAG repeat undergo apoptosis (Ikeda et al, 1996). They proposed that the expanded polyglutamine tract, but not normal polyglutamine tract, exhibits marked toxicity to COS cells, and suggested that a difference in processing of the gene products among cells of various lineages may be the reason for the difference in distribution of affected regions.…”

Mouse Models of Spinocerebellar Ataxia Type 3 (Machado-Joseph Disease)

“…The first transgenic mouse that expressed full-length mutant ataxin-3 isoform MJD1a with 79 polyglutamines under control of the L7 promoter (Purkinje cell specific) failed to develop neurological deterioration at 23 weeks of age [28]. By contrast, transgenic mice expressing a portion of such human mutant ataxin-3 containing the expanded polyglutamines and under the control of the same promoter had severe atrophy of the cerebellum, including Purkinje cell loss at 8 weeks of age, and severe ataxic behavior starting at 4 weeks of age [28]. Based on these results and cell model studies, the toxic fragment hypothesis was proposed, in which all cells express fulllength mutant ataxin-3 and affected neurons express a protease that releases the toxic fragment [28].…”

“…Generation and characterization of transgenic mice expressing mutant ataxin-3 are providing insight into the mechanisms causing the disease and facilitating the development of a therapy. Transgenic mice expressing portions of the mutant ataxin-3 age [28][29][30], and a lentiviralbased rat model expressing mutant ataxin-3 in a single brain region [24] have been reported, but these are not the focus of this review. Seven transgenic mice expressing full-length mutant ataxin-3 throughout the brain have been reported and are described as dramatically different in previous reviews [31].…”