CBBS Paper of the year 2019

SIPA1L2 steuert den Transport und die lokale Signalübertragung von TrkB-haltigen Amphisomen an präsynaptischen Endigungen

Signal molecules such as BDNF and its receptor TrkB play an important role in communication between nerve cells. Such signals must be transmitted into the cell, where they regulate gene expression in the cell nucleus, which plays a key role in both neuronal development and mature nerve cells. To convey such signals from the presynapse to the cell nucleus, the vesicles containing the signals must be transported within the axon.

Anna Karpova and Michael R. Kreutz, together with their colleagues, were able to show that this transport takes place in specialised vesicles known as amphisomes. These are  hybrid organelles that form when endosomes fuse with the outer membrane of autophagosomes. Autophagy allows cells to break down and recycle their own components. This ranges from misfolded proteins to entire cell organelles. Surprisingly, neurons organise the uptake and degradation of such waste material in spatially separate locations. Proteins are taken up in axons  and degraded in the cell body within lysosomes. This separation now allows autophagy to also play a role in neuronal signalling. 

The research team has discovered that, on their journey from the axon to the soma, amphisomes regulate plastic processes at presynaptic nerve terminals that enhance the efficiency of synaptic neurotransmission. Presumably at the same time, they clear away ‘protein waste’ and transport both signalling molecules such as the BDNF-TrkB duo and ‘damaged’ proteins. The regulatory protein SIPA1L2 plays a key role in the precise control of these processes. When it is knocked out in mice, these transport processes are disrupted, impairing the animals’ ability to learn.

This surprising discovery shows how nerve cells have elegantly resolved the negative consequences of their enormous expansion, which poses a particular challenge for the maintenance of their membranes. Membrane processes that do not interfere with one another can take place within the same vesicles.

PMID: 31784514