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Evan Reid

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.

spastin
HeLa cells depleted of spastin and labelled with markers against microtubules (red) and sorting nexin 1 (green).

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.

The Reid lab homepage

Reid lab
The Reid lab

Key papers:

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).

Dr Evan Reid

Department: Medical Genetics

contact: ealr4@cam.ac.uk

01223 336782

Plain English

Hereditary spastic paraplegias (HSPs) are a subtype of motor neuron disease, and affected people develop progressive leg paralysis because some of the longest neuronal connections (‘axons’) degenerate. HSPs are caused by mutations in specific genes, most commonly in the gene that codes for the spastin protein. Our aim is to understand how spastin normally works and how this goes wrong in HSPs. We are currently focusing on a role of spastin in regulating the transport systems in a cell, specifically in controlled cutting of the transport tracks called ‘microtubules’. This detailed understanding should inform rational treatment approaches for hereditary spastic paraplegias, and perhaps other similar neurological conditions.

 

 

Group members

Rachel Allison · James Connell · Tim Newton

Funding

Medical Research Council