Polyglutamine (polyQ) diseases, including several types of spinocerebellar ataxias and Huntington's disease (HD), are dominantly inherited neurodegenerative disorders caused by the expansion of the glutamine-coding CAG repeat in the open reading frame of the disease gene. Apart from being translated to produce toxic elongated polyQ domain-containing disease proteins, transcribed expanded CAG RNAs per se also exert toxicity in polyQ degeneration. In the R6/2 HD transgenic mouse model, expanded mutant Huntingtin (Htt) transcripts were found to physically interact with nucleolin (NCL), a nucleolar protein that plays a crucial role in ribosome biogenesis. We further demonstrated that mutant Htt transcripts deprived NCL from binding onto the Upstream Control Element (UCE) of the ribosomal RNA (rRNA) promoter. This resulted in UCE hypermethylation which abolished the binding of the transcription factor Upstream Binding Factor to UCE and subsequently led to down-regulation of pre-45s rRNA transcription. We also found that the p53/mitochondria-dependent nucleolar stress cell death pathway was activated in polyQ diseases. Ribosomal RNA transcription dysfunction has been reported in other types of neurodegenerative disorders including Alzheimer's disease; it is anticipated that nucleolar stress is one common pathogenic signaling mechanism shared by different forms of neurodegeneration.