Neurodegeneration-associated instability of ribosomal DNA

Justin Hallgren, Maciej Pietrzak, Grzegorz Rempala, Peter T. Nelson, Michal Hetman

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

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.

Original languageEnglish
Pages (from-to)860-868
Number of pages9
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1842
Issue number6
DOIs
StatePublished - Jun 2014

Bibliographical note

Funding Information:
We are grateful for the research volunteers that contributed to this work. This work was supported by the NIH ( NS073584-01 and 8P30GM103507 to MH; CA152158 to GR), the NSF ( IOS1021860 to MH; DMS1318886 to GR), the Commonwealth of Kentucky Challenge for Excellence , and the Kentucky Spinal Cord and Head Injury Research Trust . The authors wish to thank Ms. Jing-Juan Zheng for excellent technical assistance.

Keywords

  • Aging
  • Dementia with Lewy bodies
  • Genomic instability
  • Neurodegeneration
  • Nucleolus

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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