Altered expression of the Cdk5 activator-like protein, Cdk5α, causes neurodegeneration, in part by accelerating the rate of aging.
Joshua SpurrierArvind Kumar ShuklaKristina McLindenKory JohnsonEdward GinigerPublished in: Disease models & mechanisms (2018)
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.
Keyphrases
- genome wide
- cell cycle
- copy number
- dna methylation
- poor prognosis
- oxidative stress
- protein kinase
- single cell
- signaling pathway
- cell proliferation
- risk factors
- stem cells
- dna damage
- binding protein
- machine learning
- immune response
- electronic health record
- brain injury
- bone marrow
- inflammatory response
- deep learning
- artificial intelligence
- toll like receptor
- induced apoptosis
- nuclear factor
- transcription factor
- endoplasmic reticulum stress
- endoplasmic reticulum