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Icreverzi, A., de la Cruz, A.F., Walker, D.W., Edgar, B.A. (2015). Changes in neuronal CycD/Cdk4 activity affect aging, neurodegeneration, and oxidative stress.  Aging Cell 14(5): 896--906.
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Research paper

Mitochondrial dysfunction has been implicated in human diseases, including cancer, and proposed to accelerate aging. The Drosophila Cyclin-dependent protein kinase complex cyclin D/cyclin-dependent kinase 4 (CycD/Cdk4) promotes cellular growth by stimulating mitochondrial biogenesis. Here, we examine the neurodegenerative and aging consequences of altering CycD/Cdk4 function in Drosophila. We show that pan-neuronal loss or gain of CycD/Cdk4 increases mitochondrial superoxide, oxidative stress markers, and neurodegeneration and decreases lifespan. We find that RNAi-mediated depletion of the mitochondrial transcription factor, Tfam, can abrogate CycD/Cdk4's detrimental effects on both lifespan and neurodegeneration. This indicates that CycD/Cdk4's pathological consequences are mediated through altered mitochondrial function and a concomitant increase in reactive oxygen species. In support of this, we demonstrate that CycD/Cdk4 activity levels in the brain affect the expression of a set of 'oxidative stress' genes. Our results indicate that the precise regulation of neuronal CycD/Cdk4 activity is important to limit mitochondrial reactive oxygen species production and prevent neurodegeneration.

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PubMed Central ID
PMC4568977 (PMC) (EuropePMC)
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    Publication Type
    Aging Cell
    Aging Cell
    Publication Year
    1474-9718 1474-9728
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