Research


We study the molecular mechanisms underlying synaptic function, but are also interested in other aspects of intercellular communication in the nervous system.

We work primarily in Drosophila melanogaster (the fruit fly), a powerful genetic model system. By analyzing the phenotype of mutant flies, we strive to deduce the functions of the mutated proteins. We characterize the mutants functionally, for example using electrophysiological techniques; and structurally, primarily using confocal light microscopy.

 

The endophilin and PICK1 proteins

 

 

 

ENDOPHILIN

A general interest of the laboratory is proteins that contain a BAR domain. BAR domains are able to sense or change the curvature of lipid membranes, which is of major importance in membrane trafficking. We study the BAR domain containing protein endophilin, which plays a central role in the retrieval of synaptic vesicles by clathrin-dependent endocytosis.

 

 

The BAR domain of endophilin, shown as a dimer.

 

 

Synapses of Drosophila mutants that lack the gene encoding endophilin can sustain synaptic transmission at a low stimulation frequency, such as once per second. However, when challenged with higher stimulation frequencies, neurotransmission quickly fails. This is due to a block in clathrin-mediated endocytosis, caused by the lack of endophilin. 


 

 

PICK1

This is another BAR domain containing protein, which has a well-documented role in synaptic plasticity at mammalian glutamatergic synapses. We have characterized the PICK1 expression patterns in the fly and have discovered novel functions of the protein in the neuroendocrine and endocrine systems that regulate the metabolism both in flies and mammals, as described in the paper by Jansen et al. and in a recently accepted manuscript (Holst et al.)



  

THE EGGHEAD GLYCOSYLTRANSFERASE

Recently, we have characterized peripheral nerve growth in Drosophila mutants with a loss-of-function mutation in egghead, in collaboration with Hans Wandall, Copenhagen Center for Glycomics.



Electron microscopy images showing cross sections of a peripheral nerve in a wild type Drosophila larva (left) and a severely overgrown nerve characteristic of egghead mutant larvae (right).


The egghead gene encodes a glycosyltransferase catalyzing an early step in the biosynthesis of glycosphingolipids. We have found that blocking glycosphingolipid elongation leads to thickening of nerve sheaths due to overgrowth of glial cells, and accumulation of immune cells on the nerves. This is similar to neurofibromatosis, a not uncommon human inherited disease carrying an increased risk of glial cell tumors. These and related findings are described in the paper by Dahlgaard et al.

 

  

 






 

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