Date on Master's Thesis/Doctoral Dissertation

5-2014

Document Type

Master's Thesis

Degree Name

M.S.

Department

Pharmacology and Toxicology

Degree Program

Pharmacology and Toxicology, MS

Committee Chair

Hetman, Michal

Author's Keywords

Dementia with Lewy Bodies; Ribosomal DNA; Nucleolus; Genomic instability; Neurodegenerative disease

Subject

Nervous system--Degeneration--Genetic aspects; DNA

Abstract

Homologous recombination-mediated instability of the repetitively organized ribosomal DNA has been proposed as a mediator of cell senescence in yeast triggering the DNA damage response. High individual variability in the content of human ribosomal DNA suggests that this genomic region remained relatively unstable throughout evolution. Therefore, quantitative real time PCR was used to determine the genomic content of ribosomal DNA 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, ribosomal DNA content in that brain region was compared between 10 age-matched control individuals and 10 patients with dementia with Lewy bodies which involves neurodegeneration of the cerebral cortex. Probing ribosomal RNA-coding regions of ribosomal DNA revealed no effects of aging on the ribosomal DNA content. Elevated ribosomal DNA content was observed in Dementia with Lewy Bodies. Conversely, in the Dementia with Lewy Bodies pathology-free cerebellum, lower genomic content of ribosomal DNA was present in the Dementia with Lewy Bodies group. In the parietal cortex, such a Dementia with Lewy Bodies-associated instability of ribosomal DNA was not accompanied by any major changes of CpG methylation of the ribosomal DNA promoter. As increased cerebro-cortical ribosomal DNA content was previously reported in Alzheimer’s diseases, neurodegeneration appears to be associated with instability of ribosomal DNA. The hypothetical origins and consequences of this phenomenon are discussed including possibilities that the DNA damage-induced recombination destabilizes ribosomal DNA and that differential content of ribosomal DNA affects heterochromatin formation, gene expression and/or DNA damage response.

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