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.
Highlights
The correct formation and subsequent maintenance of synapses is a key prerequisite for brain development, function and longevity
We propose a new mechanism based on the loss of Tau function which could explain intellectual disability in MAPT mutant individuals and precocious synapse loss in tau-related neurodegeneration (Saxena and Caroni, 2007; Serrano-Pozo et al, 2011)
Already 8 hr in vitro (HIV), these neurons show transport of synaptic material in the growing axon (Sanchez-Soriano et al, 2010) and after 2 days in vitro (DIV), they display functional presynaptic sites (Kuppers-Munther et al, 2004; Kuppers et al, 2003) that can be reliably stained with antibodies against presynaptic proteins (Figure 1—figure supplement 1)
Summary
The correct formation and subsequent maintenance of synapses is a key prerequisite for brain development, function and longevity. The development of synapses and their maintenance during ageing is dependent on sustained transport of synaptic proteins from the distant soma, driven by motor proteins which trail along the bundles of microtubules in axons and dendrites (Goldstein et al, 2008). Microtubules are regulated by microtubule binding proteins which are in a key position to regulate synapse formation and maintenance (Prokop, 2013). Tau detachment from MTs is linked to prominent neurodegenerative diseases such as Alzheimer’s disease, Frontotemporal Dementia and some forms of Voelzmann et al eLife 2016;5:e14694.
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