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Matthew Seaman

The molecular mechanisms of endosome-to-Golgi retrieval

The endosome-to-Golgi pathway is of vital importance to normal cellular homeostasis and is linked to several pathological processes including neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson’s disease (PD) and hereditary spastic paraplegia (HSP).

The studies in my lab have primarily been focused on a complex of proteins called ‘retromer’ that is conserved across all eukaryotic species and is a key component of the endosome-to-Golgi pathway. Recently we have shown that retromer, in addition to sorting membrane proteins for retrieval to the Golgi, also acts as a hub for the recruitment of the actin polymerizing WASH complex and is thereby important for additional aspects of endosomal protein sorting including transport of proteins to the cell surface. The strumpellin component of the WASH complex is mutated in HSP and the KIAA1033 component is linked to autosomal recessive intellectual disability and also AD. One of the components of retromer is mutated in an inherited form of PD and we have been characterising the effect of the mutation on the function of the retromer complex.

Much of endosomal protein sorting involves the generation of membrane tubules into which proteins are sorted and we have been actively studying how the operation of the WASH complex is coordinated with the mechanisms that govern tubule formation and have identified a key regulatory protein that is required for normal tubule formation. To identify novel components of the endosome-to-Golgi pathway we have recently completed a genome-wide siRNA screen and have discovered several new membrane proteins that are required for endosome-to-Golgi retrieval and are candidate proteins to analyse for a role in the processes that lead to AD.

These studies will significantly enhance the understanding of mechanisms of endosomal protein sorting and lead to new insights into diseases such as AD and PD.

 

Seaman lab

Key papers:

Seaman, M.N.J. Cargo-selective endosomal sorting for retrieval to the Golgi requires retromer. J. Cell Biol. 165, 111–122 (2004).

Harbour, M.E., Breusegem, S.Y.A., Antrobus, R., Freeman, C., Reid, E. and Seaman, M.N.J. The cargo-selective retromer complex is a recruiting hub for protein complexes that regulate endosomal tubule dynamics. J. Cell Sci. 123, 3703–3717 (2010).

Vardarajan, B., Breusegem, S. Harbour, M., St George-Hyslop, P., *Seaman, M.N.J. and *Farrer, L.A. Identification of Alzheimer disease associated variants in genes that regulate retromer function. Neurobiol Aging 33, 2231.e15-2231. *co-corresponding authors (2012).

Freeman, C.L., Hesketh G. and Seaman, M.N.J. RME-8 coordinates the WASH complex with the retromer SNX-BAR dimer to control endosomal tubulation. J. Cell Sci. In Press (2014).

Zavodszky, E., Seaman, M.N.J*., Moreau, K., Jimenez-Sanchez, M., Breusegem, S.Y., Harbour, M.E. and Rubinsztein, D.C. Mutation in VPS35 associated with Parkinson’s disease impairs WASH complex association and inhibits autophagy. Nat Comms. 13;5:3828 * Joint first author and co-corresponding author (2014).

Breusegem, S.Y. & Seaman, M.N. Genome-wide RNAi screen reveals a role for multipass membrane proteins in endosome-to-Golgi retrieval. Cell Reports doi: http://dx.doi.org/10.1016/j.celrep.2014.10.053 (2014).

 

Professor Matthew Seaman

Professor of Cell and Membrane Biology

Department: Clinical Biochemistry

contact:mnjs100@cam.ac.uk

01223 763 225

Plain English

Cells are divided up into specialized compartments called organelles, each surrounded by membrane. This provides control by segregating different biological processes. Communication between these compartments is also a vital part of cell function, and this is achieved by the transport of small parcels of membrane. We focus on understanding a particular transport pathway that occurs between two organelles  — endosomes and the Golgi. We have recently identified 90 genes that control this and, by characterizing their functions, we hope to provide new insights into this transport pathway. This has broad implications, as this pathway has been linked both to neurodegenerative diseases including Alzheimer's, and to bacterial and viral infections.

Group members

Sophie Breusegem · Aamir Mukadam

Funding

Medical Research Council