The long-term goal of the proposed research is to study the mechanisms responsible for age-related degenerative processes. The understanding of these mechanisms may help to find ways to slow down the corresponding processes thus moving the onset of deterioration outside the normal human lifespan. Accumulation of mtDNA mutations has been long hypothesized as a probable cause of the various symptoms of aging, however, proof of such involvement was lacking. There is no consensus regarding which tissues and/or cell types if any are most likely to be affected. Our recent research has demonstrated unprecedented accumulation of mtDNA deletions in the substantia nigra of the aged human brain, which results in respiratory chain defects in pigmented neurons. This demonstration is important conceptually as an example the most significant involvement of somatic mtDNA mutations in an age-related degenerative process, but it also raises questions regarding the health consequences of this process, and whether it is limited to s. nigra.
The specific aims therefore are: (1) To test the hypothesis that clonal expansions of mtDNA mutations, either deletions or point mutations, cause functional defects in specific cell types of the brain, and/or cause degeneration or predispose cells to degeneration. (2) To test the hypothesis that accumulation of mtDNA deletions in pigmented neurons of substantia nigra contributes to the development of Mild Parkinsonian Signs in seniors. We will compare the prevalence of cells with mtDNA deletions in a collection of well- characterized brains with respect to the presence of parkinsonian signs. (3) To develop new methodologies for mtDNA mutation quantification in individual cells. The methods include mtDNA Fluorescent In Situ Hybridization (FISH) for quantification of mtDNA deletions, and a novel massive parallel 454 DNA sequencing approach for studying mtDNA point mutations. In short, we have discovered a novel, common, age-related degenerative process in the brain involving the DNA of mitochondria, the power plants of the cell. This process affects an area involved in Parkinson's disease. We are therefore exploring if the process is responsible for movement problems widespread among the senior population. We are also testing whether similar processes affect other parts of the aging brain. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG019787-07
Application #
7350131
Study Section
Special Emphasis Panel (ZRG1-NOMD-A (01))
Program Officer
Wise, Bradley C
Project Start
2001-09-30
Project End
2012-01-31
Budget Start
2008-03-01
Budget End
2009-01-31
Support Year
7
Fiscal Year
2008
Total Cost
$403,019
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
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Safdar, Adeel; Khrapko, Konstantin; Flynn, James M et al. (2016) Exercise-induced mitochondrial p53 repairs mtDNA mutations in mutator mice. Skelet Muscle 6:7
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Guo, Xinhong; Kudryavtseva, Elena; Bodyak, Natalya et al. (2010) Mitochondrial DNA deletions in mice in men: substantia nigra is much less affected in the mouse. Biochim Biophys Acta 1797:1159-62
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Zsurka, Gabor; Kudina, Tatiana; Peeva, Viktoriya et al. (2010) Distinct patterns of mitochondrial genome diversity in bonobos (Pan paniscus) and humans. BMC Evol Biol 10:270
Greaves, Laura C; Beadle, Nina E; Taylor, Geoffrey A et al. (2009) Quantification of mitochondrial DNA mutation load. Aging Cell 8:566-72

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