Neurodegeneration-associated instability of ribosomal DNA

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Highlights

  • Brain rDNA instability is shown in dementia with Lewy bodies but not in aging.

  • These data suggest activation of homologous recombination in neurodegeneration.

  • Methylation of the rDNA promoter is not affected by dementia with Lewy bodies.

  • Causes and consequences of rDNA instability are discussed.

Abstract

Homologous recombination (HR)-mediated instability of the repetitively organized ribosomal DNA (rDNA) has been proposed as a mediator of cell senescence in yeast triggering the DNA damage response. High individual variability in the content of human rDNA suggests that this genomic region remained relatively unstable throughout evolution. Therefore, quantitative real-time polymerase chain reaction was used to determine the genomic content of rDNA in post mortem samples of parietal cortex from 14 young and 9 elderly individuals with no diagnosis of a chronic neurodegenerative/neurological disease. In addition, rDNA content in that brain region was compared between 10 age-matched control individuals and 10 patients with dementia with Lewy bodies (DLB) which involves neurodegeneration of the cerebral cortex. Probing rRNA-coding regions of rDNA revealed no effects of aging on the rDNA content. Elevated rDNA content was observed in DLB. Conversely, in the DLB pathology-free cerebellum, lower genomic content of rDNA was present in the DLB group. In the parietal cortex, such a DLB-associated instability of rDNA was not accompanied by any major changes of cytosine–phosphate–guanine methylation of the rDNA promoter. As increased cerebro-cortical rDNA content was previously reported in Alzheimer's disease, neurodegeneration appears to be associated with instability of rDNA. The hypothetical origins and consequences of this phenomenon are discussed including possibilities that the DNA damage-induced recombination destabilizes rDNA and that differential content of rDNA affects heterochromatin formation, gene expression and/or DNA damage response. This article is part of a Special Issue entitled: Role of the Nucleolus in Human Disease.

Abbreviations

ALB
albumin
AD
Alzheimer's disease
CpG
cytosine–phosphate–guanine
DLB
dementia with Lewy bodies
DDR
DNA damage response
HR
homologous recombination
tRNAK-ctt
lysine-ctt tRNA
MCI
mild cognitive impairment
MMSE
Minimental State Examination
NoRC
nucleolar repressive complex
PD
Parkinson's disease
PMI
post mortem interval
rDNA
ribosomal DNA
rRNA
ribosomal RNA
qPCR
quantitative real-time polymerase chain reaction
SAM
significance analysis of microarrays

Keywords

Nucleolus
Genomic instability
Dementia with Lewy bodies
Neurodegeneration
Aging

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This article is part of a Special Issue entitled: Role of the Nucleolus in Human Disease.