Intranuclear Inclusions of Expanded Polyglutamine Protein in Spinocerebellar Ataxia Type 3

Abstract

The mechanism of neurodegeneration in CAG/polyglutamine repeat expansion diseases is unknown but is thought to occur at the protein level. Here, in studies of spinocerebellar ataxia type 3, also known as Machado-Joseph disease (SCA3/MJD), we show that the disease protein ataxin-3 accumulates in ubiquitinated intranuclear inclusions selectively in neurons of affected brain regions. We further provide evidence in vitro for a model of disease in which an expanded polyglutamine-containing fragment recruits full-length protein into insoluble aggregates. Together with recent findings from transgenic models, our results suggest that intranuclear aggregation of the expanded protein is a unifying feature of CAG/polyglutamine diseases and may be initiated or catalyzed by a glutamine-containing fragment of the disease protein.

Preventing polyglutamine-induced activation of c-Jun delays neuronal dysfunction in a mouse model of SCA7 retinopathy

“…This expansion results in a longer polyQ-track, which in turn leads to toxic gain-of-function and increased propensity of the expanded protein to aggregate (Scherzinger et al, 1997;Ross and Poirier, 2004). Consequently, the hallmarks of polyQ disorders are nuclear inclusions (NIs) containing aggregated mutant proteins in affected neurons (Di Figlia et al, 1997;Paulson et al, 1997;Skinner et al, 1997). Although toxicity of NIs per se can be debated, a number of studies suggest deregulation of cellular components involved in folding and/or degradation of proteins as a possible mechanism of disease pathogenesis (Warrick et al, 1999;Bence et al, 2001;Miller et al, 2005;Vacher et al, 2005;Waza et al, 2005).…”

Translation of HTT mRNA with expanded CAG repeats is regulated by the MID1–PP2A protein complex

“…Expanded CAG sequences are translated into elongated polyglutamine (polyQ) stretches. This renders the respective proteins insoluble and leads to the formation of protein aggregates [2][3][4][5][6][7] .…”

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

“…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.…”