Stress-induced Cdk5 activity enhances cytoprotective basal autophagy in Drosophila melanogaster by phosphorylating acinus at serine437.

Nilay Nandi,Helmut Krämer,Lauren K Tyra,Drew Stenesen

doi:10.7554/elife.30760

Abstract

Cdk5 is a post-mitotic kinase with complex roles in maintaining neuronal health. The various mechanisms by which Cdk5 inhibits and promotes neurodegeneration are still poorly understood. Here, we show that in Drosophila melanogaster Cdk5 regulates basal autophagy, a key mechanism suppressing neurodegeneration. In a targeted screen, Cdk5 genetically interacted with Acinus (Acn), a primarily nuclear protein, which promotes starvation-independent, basal autophagy. Loss of Cdk5, or its required cofactor p35, reduces S437-Acn phosphorylation, whereas Cdk5 gain-of-function increases pS437-Acn levels. The phospho-mimetic S437D mutation stabilizes Acn and promotes basal autophagy. In p35 mutants, basal autophagy and lifespan are reduced, but restored to near wild-type levels in the presence of stabilized AcnS437D. Expression of aggregation-prone polyQ-containing proteins or the Amyloid-β42 peptide, but not alpha-Synuclein, enhances Cdk5-dependent phosphorylation of S437-Acn. Our data indicate that Cdk5 is required to maintain the protective role of basal autophagy in the initial responses to a subset of neurodegenerative challenges.

Highlights

Cdk5 shares strong homology with other members of the family of cyclin-dependent kinases (Cdks), but it is distinct in its modes of regulation and function (Dhavan and Tsai, 2001; Pozo and Bibb, 2016)
We show that reduced Cdk5 activity can reduce neuronal fitness by compromising basal autophagy
We find that the effect of the Cdk5/p35 complex on autophagy depends on its role in phosphorylating the conserved S437 in Acn

Summary

Introduction

Cdk shares strong homology with other members of the family of cyclin-dependent kinases (Cdks), but it is distinct in its modes of regulation and function (Dhavan and Tsai, 2001; Pozo and Bibb, 2016). In post-mitotic cells, Cdk is regulated by binding to its obligatory membrane-associated p35 or p39 co-activators (Tsai et al, 1994; Tang et al, 1995). These co-activators are highly expressed in the brain and loss of Cdk activity in mice or flies has been associated with defects in neurite outgrowth (Su and Tsai, 2011; Trunova et al, 2011), neuronal migration (Nishimura et al, 2014), pre- and post-synaptic functions (Bibb et al, 1999; Li et al, 2001), the maintenance of synaptic plasticity (Hawasli et al, 2007), retinal degeneration (Kang et al, 2012), and neurodegeneration in aging brains (Trunova and Giniger, 2012; Shah and Lahiri, 2017). Cdk substrates regulating microtubule-based transport (Klinman and Holzbaur, 2015) and synaptic function (Tan et al, 2003; Lai and Ip, 2015), have been identified, but the long-term neuroprotective function of Cdk activity remains poorly understood (McLinden et al, 2012; Meyer et al, 2014)

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Conclusion