title: Changes in neuronal CycD/Cdk4 activity affect aging, neurodegeneration, and oxidative stress.
abstract: 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.
authors.affiliation: Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, CA, 90095, USA.
authors.forename: Amalia
authors.initials: A
authors.lastname: Icreverzi
authors.affiliation: Basic Science Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
authors.forename: Aida Flor A
authors.initials: AF
authors.lastname: de la Cruz
authors.affiliation: Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, CA, 90095, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Walker
authors.affiliation: German Cancer Research Center (DKFZ) & Center for Molecular Biology Heidelberg (ZMBH), Im Neuenheimer Feld 282, D-69120, Heidelberg, Germany.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Edgar
mesh_terms: D000375:Aging / Q000235:genetics; D000818:Animals; D056741:Cyclin D / Q000235:genetics / Q000378:metabolism*; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology / Q000235:genetics / Q000378:metabolism; D005260:Female; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D018384:Oxidative Stress / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C534694:CycD protein, Drosophila; D056741:Cyclin D; D029721:Drosophila Proteins; D017382:Reactive Oxygen Species; C495896:Cdk4 protein, Drosophila; D051358:Cyclin-Dependent Kinase 4
keywords: aging; mitochondria; neurodegeneration; oxidative stress; superoxide