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. We have now shown 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 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 paper describing these results has now been published, and the gene expression-based aging metric we described is now being applied by other labs to analysis of aging and degeneration in other systems, such as mouse. We have shown previously that reduced activity of Cdk5/p35 disrupts the subcellular organization of the axon, particularly the domain called the axon initial segment (AIS), where action potentials initiate. This raised the crucial question whether this effect is causally related to neuronal degeneration or is simply an unrelated, parallel effect of Cdk5. We have now developed a genetically orthogonal reagent that also disrupts the AIS, but by an independent mechanism. We find that disrupting the AIS by this alternative method, which does not share the other physiological consequences of Cdk5 inactivation, nonetheless is sufficient to cause age-dependent axonal degeneration and neuron loss. This shows that AIS disruption is indeed a causal component of the syndrome of phenotypes by which altered Cdk5 causes neurodegeneration. This discovery is of particular importance as other labs, following our lead, have now show that AIS disturbance is correlated with neurodegeneration in mouse models, though, like our earlier work, those investigators had no way to assess causality. Our data now validate these mammalian experiments as investigating a bona fide causal mechanism of degeneration. We are in the final stages of preparing for publication a manuscript that documents these findings.

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10
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2018
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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
Prithviraj, Ranjini; Trunova, Svetlana; Giniger, Edward (2012) Ex vivo culturing of whole, developing Drosophila brains. J Vis Exp :
Song, Jeong K; Giniger, Edward (2011) Noncanonical Notch function in motor axon guidance is mediated by Rac GTPase and the GEF1 domain of Trio. Dev Dyn 240:324-32
Kuzina, Irina; Song, Jeong K; Giniger, Edward (2011) How Notch establishes longitudinal axon connections between successive segments of the Drosophila CNS. Development 138:1839-49
Trunova, Svetlana; Baek, Brian; Giniger, Edward (2011) Cdk5 regulates the size of an axon initial segment-like compartment in mushroom body neurons of the Drosophila central brain. J Neurosci 31:10451-62
Song, Jeong K; Kannan, Ramakrishnan; Merdes, Gunter et al. (2010) Disabled is a bona fide component of the Abl signaling network. Development 137:3719-27