Neurodegeneration-associated instability of ribosomal DNA

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1842

Article

Hallgren, Justin^1,2,3  Pietrzak, Maciej^1,2  Rempala, Grzegorz⁴  Nelson, Peter T.⁵  Hetman, Michal^1,2,3 

[1] Univ Louisville, Kentucky Spinal Cord Injury Res Ctr, Louisville, KY 40292 USA

[2] Univ Louisville, Dept Neurol Surg, Louisville, KY 40292 USA

[3] Univ Louisville, Dept Pharmacol & Toxicol, Louisville, KY 40292 USA

[4] Ohio State Univ, Coll Publ Hlth, Div Biostat, Columbus, OH 43210 USA

[5] Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA

关键词: Nucleolus;    Genomic instability;    Dementia with Lewy bodies;    Neurodegeneration;    Aging;   

DOI  :  10.1016/j.bbadis.2013.12.012

来源: Elsevier

【 摘 要 】

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 cerebra-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. (C) 2014 Elsevier B.V. All rights reserved.

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