GAD65 Linked to Type 1 Diabetes
Tuesday, 10 June, 2014
Researchers are a step closer to establishing the link between a protein with a split personality, called GAD65, and type 1 diabetes.
New research聽shows how 聽GAD65 changes its shape when it turns itself on and off. Curiously, this characteristic may also link it to type 1 diabetes. The research was聽published 聽in the journal聽PNAS.
In the human brain, GAD65 performs an essential role: it makes 鈥榥eurotransmitters鈥 - chemicals that pass messages between brain cells.
GAD65 is also found in the pancreas. Previous studies linked it to type 1 diabetes because the body makes antibodies against the protein. However the molecular details of what makes GAD65 鈥榮ticky鈥 to antibodies has remained a mystery until now.
The new research, led by Monash University, investigated how GAD65 regulates the production of neurotransmitters by changing its shape.
Principal Investigator聽聽said the findings showed that the normal function of the protein may come at a price.
鈥淕AD65 has an unpredictable, almost Jekyll and Hyde personality when it is turned on and off. When active and making neurotransmitters, it is rigid and rather motionless. Ironically, when switched off, rather than resting as you might expect, it becomes mobile, dancing and jiggling around.
鈥淲e suspected that this dual personality might affect how antibodies 'see' it. This turns out to be true - antibodies interact with it very differently depending on whether it鈥檚 on or off," Associate Professor Buckle said.
GAD65 has previously been used in clinical trials as a vaccine for type 1 diabetes, with limited success. Associate Professor Buckle said the discovery may ultimately lead to the development of better vaccines to potentially treat and prevent type 1 diabetes.
鈥淭he idea to immunise an individual with GAD65 to help the immune system develop a tolerance against it, to stop or at least dampen the immune reaction is a good one. But so far these attempts have not been very successful. This research could change that,鈥 Associate Professor Buckle said.
The seven-year study used a combination of experimental and computational methods to understand what GAD65 looks like in its 'off' state and how human antibodies interact with both forms.
Powerful beam lines at the Australian Synchrotron, as well as massive super computers at the Victorian Life Sciences Computation Initiative (VLSCI) and Monash, were used to accelerate the research.
Associate Professor Buckle said access to world-class facilities was critical to the research.
鈥淭echniques like X-ray crystallography produce amazing, detailed pictures of large molecules, but these are often snapshots frozen in time. In order to 'see' the molecules in action we needed to combine other techniques, such as molecular simulation, to produce a movie. The Australian Synchrotron and the VLSCI played a major part in this work,鈥 Associate Professor Buckle said.
In the next phase, the research team will visualise GAD65 as it interacts with a human antibody. Understanding why GAD65 is recognised and targeted by antibodies is the next step. In addition to specific insights, it鈥檚 hoped this work will provide important basic knowledge that could be applied to broader aspects of health and medicine.
For further information please contact Lucy Handford on 03 9903 4840 or email聽lucy.handford@monash.edu
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