Intraneuronal tau aggregations are distinctive pathological features of Parkinson's disease (PD) with autosomal-dominant mutations in leucine-rich repeat kinase 2 (LRRK2). The most prevalent LRRK2 mutation, G2019S (glycine to serine substitution at amino acid 2019), causes neurite shrinkage through unclear pathogenetic mechanisms. We found that expression of G2019S mutant in Drosophila dendritic arborization neurons induces mislocalization of the axonal protein tau in dendrites and causes dendrite degeneration. G2019S-induced dendrite degeneration is suppressed by reducing the level of tau protein and aggravated by tau coexpression. Additional genetic analyses suggest that G2019S and tau function synergistically to cause microtubule fragmentation, inclusion formation, and dendrite degeneration. Mechanistically, hyperactivated G2019S promotes tau phosphorylation at the T212 site by the Drosophila glycogen synthase kinase 3␤ homolog Shaggy (Sgg). G2019S increases the recruitment of autoactivated Sgg, thus inducing hyperphosphorylation and mislocalization of tau with resultant dendrite degeneration.

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Death-associated protein kinase (DAPK) is a key player in several modes of neuronal death/injury and has been implicated in the late-onset Alzheimer's disease (AD). DAPK promotes cell death partly through its effect on regulating actin cytoskeletons. In this study, we report that DAPK inhibits microtubule (MT) assembly by activating MARK/PAR-1 family kinases MARK1/2, which destabilize MT by phosphorylating tau and related MAP2/4. DAPK death domain, but not catalytic activity, is responsible for this activation by binding to MARK1/2 spacer region, thereby disrupting an intramolecular interaction that inhibits MARK1/2. Accordingly, DAPK À/À mice brain displays a reduction of tau phosphorylation and DAPK enhances the effect of MARK2 on regulating polarized neurite outgrowth. Using a well-characterized Drosophila model of tauopathy, we show that DAPK exerts an effect in part through MARK Drosophila ortholog PAR-1 to induce rough eye and loss of photoreceptor neurons. Furthermore, DAPK enhances tau toxicity through a PAR-1 phosphorylation-dependent mechanism. Together, our study reveals a novel mechanism of MARK activation, uncovers DAPK functions in modulating MT assembly and neuronal differentiation, and provides a molecular link of DAPK to tau phosphorylation, an event associated with AD pathology.

Background: Focal adhesion kinase (FAK) functions in cell migration and signaling through activation of the mitogen-activated protein kinase (MAPK) signaling cascade. Neuronal function of FAK has been suggested to control axonal branching; however, the underlying mechanism in this process is not clear.