Altered expression of the Cdk5 activator-like protein, Cdk5?, causes neurodegeneration, in part by accelerating the rate of aging

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Abstract

Aging is the greatest risk factor for neurodegeneration, but the connection between the two processes remains opaque. This is in part for want of a rigorous way to define physiological age, as opposed to chronological age. Here, we develop a comprehensive metric for physiological age in Drosophila, based on genome-wide expression profiling. We applied this metric to a model of adult-onset neurodegeneration, increased or decreased expression of the activating subunit of the Cdk5 protein kinase, encoded by the gene Cdk5?, the ortholog of mammalian p35. Cdk5?-mediated degeneration was associated with a 27-150% acceleration of the intrinsic rate of aging, depending on the tissue and genetic manipulation. Gene ontology analysis and direct experimental tests revealed that affected age-associated processes included numerous core phenotypes of neurodegeneration, including enhanced oxidative stress and impaired proteostasis. Taken together, our results suggest that Cdk5?-mediated neurodegeneration results from accelerated aging, in combination with cell-autonomous neuronal insults. These data fundamentally recast our picture of the relationship between neurodegeneration and its most prominent risk factor, natural aging.

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CITATION STYLE

APA

Spurrier, J., Shukla, A. K., McLinden, K., Johnson, K., & Giniger, E. (2018, March 1). Altered expression of the Cdk5 activator-like protein, Cdk5?, causes neurodegeneration, in part by accelerating the rate of aging. DMM Disease Models and Mechanisms. Company of Biologists Ltd. https://doi.org/10.1242/dmm.031161

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