About the Project
www.endocytosis.org
Synaptic dysfunction has long been known to play a role in the onset of Parkinson’s. Drugs that affect neuronal synaptic function can induce Parkinsonian symptoms while mutations of the mitochondrial PINK and PARKIN proteins are found in patients with the disease.
This project aims to find out what happens to synapses when mitochondrial stop functioning optimally. We have found in fibroblast models, that a number of risk factor proteins for Parkinson’s affect mitochondrial function. We would now like to move this work from fibroblasts into neurons where mitochondria are enriched in synapses and are necessary for synaptic function. Here we will study endocytosis and exocytosis in cultured neurons while manipulation risk factors for the disease.
Understanding how mitochondria contribute to synaptic function and equally how dysfunction contributes to neuronal loss may be key to understanding the progression the disease. In addition, we hope this work will contribute useful mechanisms to be able to protect against energy deficits and thus increase neuronal health to protect against disease progression.
We will try to understand the normal function of risk factors for the disease. In addition we will be looking for new drug targets to protect against mitochondrial dysfunction.
References
Simcox, E. M., Reeve, A., & Turnbull, D. (2013). Monitoring mitochondrial dynamics and complex I dysfunction in neurons: implications for Parkinson's disease. Biochemical Society Transactions, 41(6), 1618–1624. http://doi.org/10.1042/BST20130189
Boucrot, E., …and McMahon, H.T. (2015). Endophilin marks and controls a clathrin-independent endocytic pathway. Nature, 517(7535), 460–465. http://doi.org/10.1038/nature14067
Boucrot, E., … (McMahon, H. T., & Kozlov, M. M.) (2012). Membrane fission is promoted by insertion of amphipathic helices and is restricted by crescent BAR domains. Cell, 149(1), 124–136. http://doi.org/10.1016/j.cell.2012.01.047
Llobet, A., Gallop, J. L., Burden, J. J. E., Camdere, G., Chandra, P., Vallis, Y., et al. (2011). Endophilin drives the fast mode of vesicle retrieval in a ribbon synapse. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 31(23), 8512–8519. http://doi.org/10.1523/JNEUROSCI.6223-09.2011
Peter, B. J., …. McMahon, H. T. (2004). BAR domains as sensors of membrane curvature: the amphiphysin BAR structure. Science (New York, N.Y.), 303(5657), 495–499. http://doi.org/10.1126/science.1092586
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