Molecular cell biology of axonal degeneration
Our research is focused on understanding the molecular pathology of the hereditary spastic paraplegias (HSPs). These are genetic conditions in which the axons of the corticospinal motor pathway degenerate, so their study enables precise identification of proteins that are critical for axonal health.
We want to understand the normal functions of HSP proteins and how disruption of these functions causes axonal degeneration. Many of the disease proteins function in membrane traffic processes, especially at the endoplasmic reticulum and at endosomes. Our work concentrates on understanding the functions of this membrane traffic subgroup of HSP proteins.
We primarily focus on understanding the normal and pathological functions of spastin, a microtubule severing enzyme encoded by the gene most commonly mutated in HSP. This protein is also implicated in the pathogenesis of Alzheimer's dementia, so understanding its function is of importance to common disease. Uniquely amongst microtubule severing enzymes, spastin functions at membrane sites, including endosomes and the endoplasmic reticulum (ER), where it couples microtubule severing to membrane modelling processes.
We are unravelling the mechanistic and functional roles of spastin at these locations, as we do so providing novel insights into both the causes of HSP and the purpose of microtubule severing in cells. We are systematically examining the relevance of our finding to neurons and axons. We are also exploring the relationship between spastin’s functions and that of other HSP proteins, where we are beginning to identify unifying pathological mechanisms.
Allison R, Edgar J, Pearson G, Rizo T, Newton T, Günther S, Berner F, Hague J, Connell JW, Winkler J, Lippincott-Schwartz J, Beetz C, Winner B, Reid E (2017) Defects in ER-endosome contacts impact lysosome function in hereditary spastic paraplegia. The Journal of Cell Biology, in press.
Allison, R., Lumb, J.H., Fassier, C., Connell, J.W., Ten Martin, D., Seaman, M.N.J., Hazan, J. and Reid, E. An ESCRT-spastin interaction promotes fission of recycling tubules from the endosome. J. Cell Biol. 202, 527–543 (2013).
Montenegro, G., Rebelo, A.P., Connell, J., Allison, R., Babalini, C., D'Aloia, M., Montieri, P., Schüle, R., Ishiura, H., Price, J., Strickland, A., Gonzalez, M.A., Baumbach-Reardon, L., Deconinck, T., Huang, J., Bernardi, G., Vance, J.M., Rogers, M.T., Tsuji, S., De Jonghe, P., Pericak-Vance, M.A., Schöls, L., Orlacchio, A., Reid, E.* and Züchner, S. Mutations in the ER-shaping protein reticulon 2 cause the axon-degenerative disorder hereditary spastic paraplegia type 12. J. Clin. Invest. 122, 538–544 (2012). *Joint Corresponding/Senior Author.
Blackstone, C., O’Kane, C.J. and Reid, E. Hereditary Spastic Paraplegias: Membrane Traffic and the Motor Pathway. Nature Rev. Neurosci. 12, 31–42 (2011).