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Dis Model Mech. 2018 Mar 8;11(3). pii: dmm031161. doi: 10.1242/dmm.031161.

Altered expression of the Cdk5 activator-like protein, Cdk5α, causes neurodegeneration, in part by accelerating the rate of aging.

Author information

1
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 02892, USA.
2
The Johns Hopkins University/National Institutes of Health Graduate Partnership Program, National Institutes of Health, Bethesda, MD 02892, USA.
3
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 02892, USA ginigere@ninds.nih.gov.

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 Cdk5α, the ortholog of mammalian p35. Cdk5α-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 Cdk5α-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.

KEYWORDS:

Aging; Cdk5; Cdk5α; Drosophila; Neurodegeneration; p35

PMID:
29469033
PMCID:
PMC5897722
DOI:
10.1242/dmm.031161
[Indexed for MEDLINE]
Free PMC Article

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