Steinunn Baekkeskov, PhD
Dr. Baekkeskov’s research focuses on the structure, function, cell biology and immunopathology of three autoantigens in type 1 diabetes, the GABA synthesizing enzyme glutamate decarboxylase 65 (GAD65), a tyrosine phosphatase of unknown function, IA-2, and a glycosilated islet cell membrane antigen, glima 38 of unknown function. These proteins are intracellular membrane proteins, which are expressed in pancreatic ß cells and neurons. They are targets of autoimmune processes associated with destruction of pancreatic ß cells and development of type 1 diabetes. GAD65 is also a target of autoimmunity involved in a rare neurological disorder, stiff-man syndrome. In pancreatic ß cells and neurons, GAD65 is synthesized as a hydrophilic molecule, which undergoes post-translational modifications to become membrane anchored. The Baekkeskov group has shown that a membrane anchoring signal and a Golgi targeting signal mediate the anchoring of the protein to the cytosolic face of Golgi membranes. In neurons, a palmitoylated trafficking signal regulates the exit of GAD65 from the trans-Golgi network to sorting endosomes where it enters a novel pathway that selectively targets the protein to presynaptic clusters in axon termini. The Baekkeskov lab studies this novel pathway in ß cells and neurons and its role in targeting of the three autoantigens.
GAD65 synthesizes the inhibitory signaling molecule, GABA in neurons and in pancreatic ß cells. In the brain, the Baekkeskov lab has shown that GABA synthesized by GAD65 is required for fine tuning of inhibitory neurotransmission. The function of GABA in the pancreatic ß cell is, however, less clear. Results obtained in a transgenic mouse model expressing elevated levels of GAD65 and GABA in ß cells suggest that GABA secreted by ß cells is an autocrine inhibitor of first phase insulin secretion. The Baekkeskov lab is studying the mechanism by which GABA exerts this inhibition.
Circulating autoantibodies to GAD65, IA-2, and/or glima 38 can be detected several years before clinical onset of type 1 diabetes, and can be used to detect individuals at risk of developing the disease. Furthermore, these proteins can potentially be used for immune therapeutic purposes to block or prevent autoimmune ß cell destruction. The Baekkeskov lab is developing a new animal model of type 1 diabetes to facilitate the development of antigen specific immune preventive methods to halt or block ß cell destruction and development of diabetes.