CAG expansion induces nucleolar stress in polyglutamine diseases

Abstract

The cell nucleus is a major site for polyglutamine (polyQ) toxicity, but the underlying mechanisms involved have yet been fully elucidated. Here, we report that mutant RNAs that carry an expanded CAG repeat (expanded CAG RNAs) induce apoptosis by activating the nucleolar stress pathway in both polyQ patients and transgenic animal disease models. We showed that expanded CAG RNAs interacted directly with nucleolin (NCL), a protein that regulates rRNA transcription. Such RNA-protein interaction deprived NCL of binding to upstream control element (UCE) of the rRNA promoter, which resulted in UCE DNA hypermethylation and subsequently perturbation of rRNA transcription. The down-regulation of rRNA transcription induced nucleolar stress and provoked apoptosis by promoting physical interaction between ribosomal proteins and MDM2. Consequently, p53 protein was found to be stabilized in cells and became concentrated in the mitochondria. Finally, we showed that mitochondrial p53 disrupted the interaction between the antiapoptotic protein, Bcl-xL, and the proapoptotic protein, Bak, which then caused cytochrome c release and caspase activation. Our work provides in vivo evidence that expanded CAG RNAs trigger nucleolar stress and induce apoptosis via p53 and describes a polyQ pathogenic mechanism that involves the nucleolus.Drosophila | Machado-Joseph disease | RNA toxicity | spinocerebellar ataxia

Inhibition of Autophagy via p53-Mediated Disruption of ULK1 in a SCA7 Polyglutamine Disease Model

“…Several studies have implicated altered p53-mediated transcriptional activity and apoptosis in polyQ diseases (Bae et al, 2005;Chou et al, 2011;Grison et al, 2011;Illuzzi et al, 2011;Shahbazian et al, 2001;Steffan et al, 2000;Tsoi et al, 2012;Wang et al, 2010). However, to our knowledge no studies investigating the effects of mutant polyQ proteins on p53-mediated regulation of autophagy have so far been published.…”

“…As p53 is a known autophagy regulator and altered p53 activity has been implicated in polyQ pathology, we examined the level and sub-cellular localization of p53 in FLQ10 and FLQ65 cells (Bae et al, 2005;Chou et al, 2011;Grison et al, 2011;Illuzzi et al, 2011;Shahbazian et al, 2001;Steffan et al, 2000;Tsoi et al, 2012;Wang et al, 2010). In FLQ10 cells p53…”

Targeting CAG repeat RNAs reduces Huntington’s disease phenotype independently of huntingtin levels

“…The most recent advances in understanding HD pathogenesis have revealed the coexistence of mutant protein toxicity and detrimental activity of mutant/expanded CAG RNAs (5)(6)(7)(8)(9). Long CAG-trinucleotide repeats form RNA stable hairpin structures (10), with the stem portion presenting protein-binding properties (8,11).…”

The nucleolus fine-tunes the orchestration of an early neuroprotection response in neurodegeneration

“…1,2 Impaired nucleolar activity-or nucleolar stress-may occur at early neurodegenerative disease stages and contribute to pathogenesis. [3][4][5] In post-mortem specimens of human Huntington's disease (HD), insoluble aggregates of huntingtin-a hallmark of this disorder-are found in the nucleolus, 6 which may be linked to impaired rDNA transcription, nucleolar dysfunction and specific degeneration of the striatum. An intriguing role of the nucleolus in cellular homeostasis is its participation in sensing cellular stress signals and transmitting them to the p53 stabilization system.…”