We previously developed a Drosophila model of mammalian neurodegenerative disease by inactivating the protein kinase Cdk5/p35. This is the fly homolog of one of the main proteins responsible for phosphorylating tau into the form found in the neurofibrillary tangles that are characteristic of many forms of human neurodegeneration. In the past year, we have found that in the fly, as in mouse and human, degenerative physiological phenotypes and frank neuronal death are produced not just by loss-of-function of the kinase, but also from modest hyperactivation (from 2-3x overexpression of the stimulatory subunit, expressed in the wild type temporal and spatial pattern). We have also made a fundamental advance in our understanding of the relationship of neurodegeneration to organismal aging. Various physiological measurements suggested that the process of degeneration closely resembles acceleration of various aspects of normal aging. We therefore used a combination of genome-wide expression profiling and machine learning statistical methods to develop a novel metric for physiological aging, using the internal transcriptomic state of the animal as a measure of effective age (rather than simple clock-time since birth). This metric shows conclusively that both gain and loss of function of Cdk5 kinase significantly accelerates the intrinsic rate of aging of the adult fly. Moreover, the aging-like processes that are accelerated by altering Cdk5 activity are precisely the core processes commonly associated with neurodegeneration, including oxidative stress, proteostasis, innate immunity and others. This raises the possibility that defects in these processes, rather than being causes of degeneration, are actually second-order consequences of the associated acceleration of aging, making them far less attractive as potential targets for biomarker development and drug design in neurodegenerative disease. A manuscript describing these studies has been submitted for publication and is currently under review.

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9
Fiscal Year
2017
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Spurrier, Joshua; Shukla, Arvind Kumar; McLinden, Kristina et al. (2018) Altered expression of the Cdk5 activator-like protein, Cdk5?, causes neurodegeneration, in part by accelerating the rate of aging. Dis Model Mech 11:
Trunova, Svetlana; Giniger, Edward (2012) Absence of the Cdk5 activator p35 causes adult-onset neurodegeneration in the central brain of Drosophila. Dis Model Mech 5:210-9
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