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

Disease Models & Mechanisms
Joshua SpurrierEdward Giniger

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.

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Citations

Aug 20, 2019·Cellular and Molecular Life Sciences : CMLS·Eva QuandtJosep Clotet
Sep 29, 2019·Journal of Neuromuscular Diseases·Danique BeijerVincent Timmerman
Jul 23, 2019·The International Journal of Neuroscience·Krishna Kant Gupta, Sanjeev Kumar Singh

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Methods Mentioned

BETA
dissection
Fluorescence microscopy
Protein assay
PCA
PCR

Software Mentioned

GraphPad PRISM
Rad
GeneChip Operation Software
IMARIS
DAVID
Database for Annotation , Visualization and Integrated Discove...
Bitplane
Bio
R

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