Cdk5 dysfunction increases the intrinsic rate of aging

Authors

• JM Spurrier
• A Shukla
• E Giniger

Abstract

Aging is a major risk factor for neurodegenerative diseases (NDDs), but why? What is the relationship between aging and degeneration? To address this, I used a model of adult-onset neurodegeneration in flies. In Drosophila, Cdk5 activity requires an activating subunit p35, and either deletion or overexpression (OE) of p35 leads to multiple neurodegenerative phenotypes, including neuron loss, motor defects, and shortened lifespan. These phenotypes occur in wild type flies, but happen at an earlier chronological age in mutants. Thus, we asked if altering Cdk5 activity could accelerate the intrinsic rate of aging. I used whole-genome microarrays to quantify RNA expression from head and thorax of control flies at Day 3 (D3), D10, D30, and D45, hypothesizing that an RNA profile could be a metric for physiological age. Upon comparing the expression profile of pre-symptomatic D10 p35-null or OE mutant flies to this control profile, both mutants had an expression pattern least like age-matched control flies, and more strongly correlated with that of older control flies. Gene ontology showed aging and Cdk5 dysfunction affect similar categories, including mitochondria/redox, protein synthesis, metabolism, and proteasome function, suggesting Cdk5 dysfunction disrupts many of the same processes as aging. This effect is observed both with head and thorax tissue. Thus, it seems that Cdk5 dysfunction in the nervous system accelerates aging-related processes systemically, and not just in the brain. These findings suggest a novel relationship of aging to NDDs, and have profound implications for identifying which aspects of NDDs could be productive targets for therapy.

Scientific Focus Area: Neuroscience

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