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

eLife digest

Nerve cells form cable-like projections called axons that connect to other nerve cells to form the nervous system. Axons carry nerve impulses in the form of electrical messages, and they pass on these messages to other cells at junctions known as synapses. Specific patterns of connections between axons allow us to coordinate our movements, feel emotions and think. In Alzheimer’s disease and other neurodegenerative conditions, synapses often decay earlier than they should, which can cause important connections between nerve cells to be lost.

To be able to make and maintain synapses, nerve cells transport materials from the main body of the cell along axons to the sites where synapses form. A protein called Tau and a family of proteins called the spectraplakins are linked to neurodegenerative diseases. Changes (or mutations) in these proteins were known to disrupt the formation and maintenance of synapses, but it was not clear how these proteins work in this context.

Voelzmann et al. studied Tau and spectraplakin during synapse formation and maintenance in fruit flies. The experiments show that both proteins stabilise tube-like structures called microtubules in axons, which provide structural support to cells. The loss of Tau or spectraplakins causes the microtubules to fall apart and triggers an internal stress signalling pathway known as the JNK pathway. Activating JNK signalling blocks the transport of synaptic materials along axons, which prevents the formation of new synapses and starves existing synapses leading to their decay.

The next step is to find out whether Tau and spectraplakins play similar roles in the nerve cells of mammals, which may open up new opportunities to develop therapies for Alzheimer's and other neurodegenerative diseases.

DOI: http://dx.doi.org/10.7554/eLife.14694.002