Scientists from the Freie Universität Berlin have identified mechanisms regulating chemical neurotransmission in the nervous system.
Scientists from the Freie Universität Berlin and the NeuroCure Cluster of Excellence, led by Volker Haucke in collaboration with colleagues from the Leibniz Institute for Molecular Pharmacology (FMP) in Berlin, have unravelled a mechanism involved in the reformation of neurotransmitter containing membrane vesicles in the brain. Perturbations of this reformation process, because of mutations in key proteins such as CALM and AP180, are a possible cause for the development of neurodegenerative disorders such as Alzheimer's disease.
These results were published in the latest online issue of the Proceedings of the National Academy of Sciences (PNAS).
Signal transmission in the nervous system is mediated by the exocytic release of chemical messengers from synaptic vesicles, small 40 nm sized membrane blebs (a nanometer equals as little as 1/billion of a meter) that are localized to nerve endings at special contact sites between nerve cells termed synapses. In order to maintain neurotransmission over extended periods of time these synaptic vesicles need to be reformed within seconds and with the correct composition.
How synaptobrevin, a key factor in exocytic neurotransmitter release and a target for neurotoxins such as tetanus toxin or the anti-aging compound Botox, is sorted to synaptic vesicles is unknown. Scientists Volker Haucke and his graduate student Seong Joo Koo now have identified two proteins, AP180 and CALM, that recognize a "postal code" within synaptobrevin, thereby guiding its sorting to synaptic vesicles. With the aid of nuclear magnetic resonance spectroscopy and biochemical approaches the scientists were able to decode the molecular details of the recognition process and to visualize synaptobrevin sorting in living neurons.
"Our results not only allow us to gain novel fundamental insights into the mechanisms that allow nerve cells to sustain high-frequency signaling without fatiguing, but they may also open new therapeutic avenues for the treatment of neurodegenerative disorders," explains NeuroCure scientist Volker Haucke. Human mutations within the protein CALM, a crucial factor mediating sorting of synaptobrevin to synaptic vesicles is implicated in neurodegenerative disorders such as Alzheimer's disease.
- S. J. Koo, S. Markovic, D. Puchkov, C. C. Mahrenholz, F. Beceren-Braun, T. Maritzen, J. Dernedde, R. Volkmer, H. Oschkinat, V. Haucke. SNARE motif-mediated sorting of synaptobrevin by the endocytic adaptors clathrin assembly lymphoid myeloid leukemia (CALM) and AP180 at synapses. Proceedings of the National Academy of Sciences, 2011; DOI: 10.1073/pnas.1107067108
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