Presynaptic mechanisms in neurodegenerative disorders

Synapses have recently been found critical in the early pathogenetic changes taking place in tauopathies, including Alzheimer´s disease (AD).

They have been implicated in the spread of misfolded tau in the brain, and nerve terminals have been found to be sites of direct tau toxicity.

It is thus important to determine how tau undergoes posttranslational modifications and misfolding in nerve terminals and how misfolded tau can be degraded at this site.Building on our recent demonstration of liquid-liquid phase separation (LLPS) in nerve terminals, we will now investigate whether tau can undergo LLPS and misfolding in this location.

To determine how misfolded tau can be cleared from nerve terminals we will examine the role of different autophagy pathways, the ubiquitin-proteasome system and the retromer complex in the degradation of tau.

We will use powerful model systems, including a giant model synapse to inactivate proteins by presynaptic microinjection; mouse neurons to study presynaptic protein-protein interactions, protein aggregation, and synapse degeneration in vivo; as well as in vitro systems to examine modification of proteins following LLPS.This research can give novel information about how tau, a key pathogenic protein in the brain, becomes misfolded in nerve terminals, and how it is cleared from this site.

This knowledge can form a ground for development of new therapeutic principles that spare synapses in AD and other tauopathies. (Estimated time 5-years).