August 16, 2011 - Alzheimer's disease and frontotemporal lobar degeneration (FTLD) are two of the most prevalent forms of neurodegenerative disorders. In a study published online today in Genome Research (www.genome.org), researchers have analyzed changes in gene expression in the aging and diseased brain, finding new clues to the biology of normal aging and neurodegenerative diseases.
Recent studies have identified changes in how genes are read, or expressed, in the brain either during aging or with neurodegenerative disease. However, no previous study had directly compared gene expression changes in healthy aging with those in diseased individuals.
In this report, an international team of researchers analyzed and compared changes in gene expression associated with aging and disease in a region of the brain known to be affected in both Alzheimer's and FTLD. Comparing samples from healthy individuals ranging from 16 to 102 years old with samples from diseased individuals, the investigation uncovered striking similarity in the changes in gene expression patterns associated with aging and the neurodegenerative diseases.
"Surprisingly, these [diseased] samples contained the same aging-related changes as healthy individuals over the age of 80," said Dr. Jernej Ule of the MRC Laboratory of Molecular Biology, senior author of the study.
"Aging-related changes were apparent in the diseased individuals as young as 50 years," noted Dr. James Tollervey of the MRC Laboratory of Molecular Biology, the first author of the study, "roughly 25 years before we would expect to see similar changes in healthy individuals."
While the similarities were striking, the group also observed notable differences between gene expression in the normal aging brain and expression in Alzheimer's and FTLD, particularly in the patterns of alternative splicing, a process by which parts of a RNA molecule are arranged differently to change the message, which can be potentially harmful if misregulated.
In normal aging, changes in alternative splicing largely affected genes associated with cellular metabolism, while disease-specific changes were associated with genes involved in neuron-specific function. The group found that there were changes in the expression of several genes coding for RNA binding proteins, which is likely responsible for at least part of the observed alterations in splicing.
The authors expect that this work will have broad impact for further insight into both normal aging and neurodegenerative disease. "These findings indicate that studies of healthy aging could help unravel the processes that lead to neurodegeneration," said Ule.
"Conversely, our findings also indicate that studies of neurodegenerative diseases might help us understand how to delay the changes that take place in healthy individuals at an advanced age," added Dr. Boris Rogelj of the MRC Centre for Neurodegeneration Research at King's College London, a co-author of the study
Scientists from the MRC Laboratory of Molecular Biology (Cambridge, UK), the MRC Centre for Neurodegeneration Research (London, UK), the EMBL-European Bioinformatics Institute (Hinxton, UK), Affymetrix, Inc. (Santa Clara, CA), and the University of Ljubljana (Ljubljana, Slovenia) contributed to this study.
This work was supported by the European Research Council, the Medical Research Council, the Slovenian Research Agency, and a Wellcome Trust and Medical Research Council Strategic Grant Award.
Dr. Jernej Ule has agreed to be contacted for more information (firstname.lastname@example.org, +44 1223402417).
Interested reporters may obtain copies of the manuscript from Peggy Calicchia, Administrative Assistant, Genome Research (email@example.com; +1-516-422-4012).
About the article:
The manuscript will be published online ahead of print on Tuesday, August 16, 2011. Its full citation is as follows: Tollervey JR, Wang Z, Hortobágyi T, Witten JT, Zarnack K, Kayikci M, Clark TA, Schweitzer AC, Rot G, Curk T, Zupan B, Rogelj B, Shaw CE, Ule J. Analysis of alternative splicing associated with aging and neurodegeneration in the human brain. Genome Res doi: 10.1101/gr.122226.111.
About Genome Research:
Launched in 1995, Genome Research (www.genome.org) is an international, continuously published, peer-reviewed journal that focuses on research that provides novel insights into the genome biology of all organisms, including advances in genomic medicine. Among the topics considered by the journal are genome structure and function, comparative genomics, molecular evolution, genome-scale quantitative and population genetics, proteomics, epigenomics, and systems biology. The journal also features exciting gene discoveries and reports of cutting-edge computational biology and high-throughput methodologies.
About Cold Spring Harbor Laboratory Press:
Cold Spring Harbor Laboratory is a private, nonprofit institution in New York that conducts research in cancer and other life sciences and has a variety of educational programs. Its Press, originating in 1933, is the largest of the Laboratory's five education divisions and is a publisher of books, journals, and electronic media for scientists, students, and the general public.
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