Tau and spectraplakins promote synapse formation and maintenance through Jun kinase and neuronal trafficking

Abstract

The mechanisms regulating synapse numbers during development and ageing are essential for normal brain function and closely linked to brain disorders including dementias. Using Drosophila, we demonstrate roles of the microtubule-associated protein Tau in regulating synapse numbers, thus unravelling an important cellular requirement of normal Tau. In this context, we find that Tau displays a strong functional overlap with microtubule-binding spectraplakins, establishing new links between two different neurodegenerative factors. Tau and the spectraplakin Short Stop act upstream of a three-step regulatory cascade ensuring adequate delivery of synaptic proteins. This cascade involves microtubule stability as the initial trigger, JNK signalling as the central mediator, and kinesin-3 mediated axonal transport as the key effector. This cascade acts during development (synapse formation) and ageing (synapse maintenance) alike. Therefore, our findings suggest novel explanations for intellectual disability in Tau deficient individuals, as well as early synapse loss in dementias including Alzheimer’s disease.DOI: http://dx.doi.org/10.7554/eLife.14694.001

Periodic actin structures in neuronal axons are required to maintain microtubules

“…There was a 4.5-fold increase in MT breaks or gaps upon 4-h treatment with 800 nM CytoD (4–8 HIV) and a ninefold increase when the CytoD dose was doubled to 1.6 µM (Figure 5, C and D). These gaps usually reflect unstable MTs and were previously reported to occur under strong MT-destabilizing conditions (Voelzmann et al , 2016b). Of importance, these effects of CytoD reverted when the drug was washed out during a 4-h period (red arrow in Figure 5D), suggesting that F-actin mediates some sustained and acutely acting function in MT maintenance.…”

“…We focus on the cytoskeleton and its immediate regulators, which have prominent hereditary links to neurodegenerative disorders (Prokop et al , 2013). Of particular importance are parallel bundles of microtubules (MTs), which run the length of axons; they need to be actively maintained because they form the structural backbones of axons and highways for life-sustaining transport of materials, organelles, and signals between cell bodies and the distal synaptic endings (Prokop, 2013; Voelzmann et al , 2016b). …”

Simulating tubulin-associated unit transport in an axon: using bootstrapping for estimating confidence intervals of best-fit parameter values obtained from indirect experimental data

“…In terms of the tau flux at the terminal, some published data suggest that tau is required for synapse maintenance [41]. We, therefore, assumed that a portion of tau that reaches the terminal eventually degrades at the terminal; the rest is reflected back.…”

Spectraplakin family proteins – cytoskeletal crosslinkers with versatile roles

“…Here, Tau and Shot act upstream of a three-step regulatory cascade, in which MTs activate JNK signaling, which in turn regulates kinesin-3-mediated axonal transport to ensure adequate delivery of synaptic proteins. This cascade acts both during development (synapse formation) and aging (synapse maintenance) (Voelzmann et al, 2016). These findings might explain the intellectual disability in Tau-deficient individuals, as well as early synapse loss in patients suffering dementia, such as those with Alzheimer's disease.…”