Peter Scott McPherson, PhD
James 平特五不中 Professor of Neurology and Neurosurgery and Anatomy and Cell Biology
Peter S. McPherson听(PhD, FRSC), is a James 平特五不中 Professor of Neurology and Neurosurgery and Anatomy and Cell Biology at The Neuro where he is the Director of the Neurodegenerative Disease Research Group. He is also a Fellow of the Royal Society of Canada and recently was appointed director of the Proteomics platform at the RI MUHC.
The McPherson laboratory uses biochemical, molecular, structural, genetic and cellular approaches to identify and functionally characterize proteins that operate in the formation of clathrin-coated vesicles (CCVs). CCVs are the major vehicles for endocytic uptake of multiple protein and lipid cargo including nutrient and signaling receptors. Following endocytosis, cargo is delivered to endosomes from where it either recycles back to the cell surface or is targeted to lysosomes for degradation. These sorting decisions control the localization and levels of proteins and are altered in cancer and neurological disease. For example, current projects in the lab reveal how disruption in transport of selective cargo from endosomes to the cell surface contributes to the development of glioblastoma and breast cancer.
McPherson's laboratory previously used subcellular proteomics (subcellular fractionation coupled to high throughput mass spectrometry) to identify the full complement of proteins that define CCVs from several tissues. A significant number of the proteins identified were uncharacterized open-reading frames. McPherson's laboratory has characterized the function of a number of these novel proteins although a significant number remain unstudied. One recently identified protein contains a module called a DENN domain. McPherson and his colleagues have demonstrated that DENN domains function enzymatically as guanine-nucleotide exchange factor to activate small GTPase of the Rab family. There are minimally 26 DENN domain proteins in the human genome and an important area of study in the laboratory involves the relationship of these proteins to the ~70 Rabs that function in membrane traffic. One particularly striking example is C9orf72, a DENN domain protein of unknown function. A mutation in C9orf72 is the most common cause of genetic forms of amyotrophic lateral sclerosis (ALS)听 and the laboratory is working to understand the relationship between endosomal membrane trafficking and disease pathogenesis.
Other proteins identified and or studied in the McPherson laboratory have been linked to other neurological diseases including Huntington disease, autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), and Parkinson disease (PD). For example, we recently demonstrated that the major PD gene LRRK2 binds to clathrin and functions in endosomal membrane trafficking. Moreover, we showed that ARSACS shares pathophysiology with PD. In fact, alterations in the regulation of membrane trafficking is emerging as a central theme in neurodegenerative diseases. Understanding the cell biological basis of neurological disease is a new focus of the laboratory.
Neurodegenerative Disorders
Xu, J., Fotouhi, M., and听McPherson, P.S.听(2015) Phosphorylation of the exchange factor DENND3 by ULK in response to starvation activates Rab12 and induces autophagy.听EMBO Reports听16: 709-718.听(Featured in the Faculty of 1000)
Ioannou, M.S., Bell, E.S., Girard, M., Chaineau, M., Hamlin, J.N.R., Daubaras, M., Monast, A., Park, M., Hodgson, L., and听McPherson, P.S. (2015) DENND2B activates Rab13 at the leading edge of migrating cells and promotes metastatic behavior.听J. Cell Biol. 208: 629-648. (Featured in a听JCB听Podcast called biobytes, in which the journal听highlights one significant paper appearing in each issue. A听movie from this manuscript, imaging Rab13 activation at the leading edge of a migrating cell, was posted by the Journal on their Facebook page and received > 34,000 views.听Featured in the Faculty of 1000).
Schreij, A.M.A., Chaineau, M., Ruan, W., Lin, S., Barker, P.A., Fon, E.A., and听McPherson, P.S. (2015) LRRK2 functions in concert with clathrin-light chains to limit Rac1 activation and control actin cytoskeleton dynamics.听EMBO Reports. 16: 79-86.
Hamlin, J.N.R., Schroeder, L., Fotouhi, M., Dokainish, H., Ioannou, M.S., Girard, M., Melan莽on, P., and听McPherson, P.S.听(2014) Scyl1 scaffolds class II Arfs to selective subcomplexes of coatomer through the gamma-COP appendage domain.听J. Cell Sci.听127: 1454-1463 (Highlighted in the 鈥淚n This Issue鈥� feature of the听Journal of Cell Science).
Vilari帽o-G眉ell, C., Rajput, A., Milnerwood, A.J., Shah, B., Szu-Tu, C., Trinh, J., Yu, I., Encarnacion, M., Munsie, L.N., Tapia, L., Gustavsson, E.K., Chou, P., Evans, D.M., Pishotta, F.T., Volta, M., Beccano-Kelly, D., Thompson, C., Lin, M.K., Guenther, B.L., Wasserman, W.W., Bernard, V., Appel-Cresswell, S., Stoessl, A.J., Robinson, C.A., Dickson, D.W., Ross, O.A., Wszolek, Z.K., Aasly, J.O., Wu, R.M., Hentati, F., Gibson, R.A.,听McPherson, P.S., Girard, M., Rajput, M., Rajput, A.H., and Farrer, M.J. (2014) DNAJC13 mutations in Parkinson Disease.听Hum. Mol. Genet. 23: 1794-1801.
Wu, Y., O鈥橳oole, E.T., Girard, M., Ritter, B., Messa, M., Liu, X.,听McPherson, P.S., Ferguson, S.M. and De Camilli, P. (2014) A dynamin 1-, dynamin 3- and clathrin-independent pathway of synaptic vesicle recycling mediated by bulk endocytosis.听Elife听 e01621. doi: 10.7554.
Ritter, B, Murphy, S., Dokainish, H., Girard, M., Gudheti, M.V., Koslov, G., Halin, M., Philie, J., Jorgensen, E.M., Gehring, K., and听McPherson, P.S.听(2013) NECAP 1 regulates AP-2 interactions to control vesicle size, number and cargo during clathrin-mediated endocytosis.听PLoS Biology. 11: e1001670.
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Allaire, P.D., Seyed Sadr, M., Chaineau, M., Seyed Sadr, E., Konefal, S., Maret, D., Fotouhi, M., Ritter, B. Del Maestro, R.F. and听McPherson, P.S. (2013) Interplay between Rab35 and Arf6 controls cargo recycling to coordinate cell adhesion and migration.听J. Cell Sci. 126: 722-731.听(Highlighted in the 鈥淚n This Issue鈥� feature of the听Journal of Cell Science).
Girard, M., Larivi猫re, R., Parfitt, D.A., Deane, E.C., Gaudet, R., Nossova, N., Blondeau, F., Prenosil, G., Vermeulen, E.G.M., Duchen, M.R., Richter, A., Shoubridge, E.A., Gehring, K., McKinney, R.A., Brais, B., Chapple, J.P. and听McPherson, P.S.听(2012) Mitochondrial dysfunction and Purkinje cell loss in Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS).听Proc. Natl. Acad. Sci., USA听109: 1661-1666. (Selected as Novel and Newsworthy when presented at the American Society for Cell Biology, December 2011, coverage in multiple newspapers including a full-page feature in the Globe & Mail, reported by multiple radio and TV stations, subject of a听Nature News and Views, Narenda, D.P. and Youle, R.J. (2012) Neurodegeneration: Trouble in the cell's powerhouse,听Nature,听483: 418-419).
Marat, A., Dokainish, H. and听McPherson, P.S.听(2011) DENN domain proteins: regulators of Rab GTPase听J. Biol. Chem.听286: 13791-13800 (invited minireview)
Allaire, P.D., Marat, A.L., Dall'Armi, C., Di Paolo, G.,听McPherson, P.S.*, and Ritter, B*. (2010) The connecdenn DENN domain: A GEF for Rab35 mediating cargo-specific exit from early endosomes.听Mol. Cell.听37: 370-382. *=co-corresponding author.
Katoh, Y., Ritter, B., Gaffry, T., Blondeau, F., H枚ning, S., and听McPherson, P.S.听(2009) The clavesin family: neuron-specific lipid- and clathrin-binding Sec14 proteins regulating lysosomal morphology.听J. Biol. Chem.听284: 27646-27654.
Burman, J.L., Bourbonniere, L., Philie, J., Stroh, T., Dejgaard, S.Y., Presley, J.F. and听McPherson, P.S.听(2008) Scyl1, mutated in a recessive form of spinocerebellar neurodegeneration, regulates COPI-mediated retrograde traffic.听J. Biol. Chem.听283:22774-22786. (selected as a JBC paper of the week)
Poupon, V., Girard, M. Legendre-Guillemin, V., Thomas, S., Bourbionniere, L., Philie, J., Bright, N.A. and听McPherson, P.S.听(2008) Clathrin-light chains function in mannose phosphate receptor trafficking via regulation of actin assembly.听Proc. Natl. Acad. Sci., USA,听105:168-173. (selected by the Faculty of 1000)
Allaire, P.D., Ritter, B., Thomas, S., Burman, J.L., Denisov, A.Yu., Legendre-Guillemin, V., Harper, S.Q., Davidson, B.L., Gehring, K. and听McPherson, P.S.听(2006) Connecdenn, a novel DENN domain-containing protein of neuronal clathrin-coated vesicles functioning in synaptic vesicle endocytosis听J. Neurosci.听26:13,202-13,212.
Girard, M., Allaire, P.D.,听McPherson, P.S*., and Blondeau, F*. (2005). Non-stoichiometric relationship between clathrin heavy and light chains revealed by subcellular proteomics of clathrin-coated vesicles from brain and liver.听Mol. Cell Proteomics.听4:1145-1154. *=co-corresponding author.
Blondeau, F., Ritter, B., Allaire, P.D., Wasiak, S., Girard, M., Hussain, N.K., Angers, A., Legendre-Guillemin, V., Roy, L., Boismenu, D., Kearney, R.E., Bell, A.W., Bergeron, J.J.M., and听McPherson, P.S.听(2004) Tandem mass spectrometry analysis of brain clathrin-coated vesicles reveals their critical involvement in synaptic vesicle recycling.听Proc. Natl. Acad. Sci., USA听101:3833-3838. (selected by the Faculty of 1000)
Ritter, B., Philie, J., Girard, M., Tung, E.C., Blondeau, F., and听McPherson, P.S.听(2003) Identification of a family of endocytic proteins that define a new alpha-adaptin ear-binding motif.听EMBO Reports听4:1089-1093.
Wasiak, S., Legendre-Guillemin, V., Puertollano, R., Blondeau, F., Girard, M., de Heuvel, E., Hussain, N.K., Boismenu, D., Bell, A.W., Bonifacino, J.S. and听McPherson, P.S.听(2002) Enthoprotin, a novel clathrin-associated protein identified through subcellular proteomics.听J. Cell Biol.158:855-862.
Metzler, M., Legendre-Guillemin, V., Gan, L., Chopra, V., Kwok, A.,听McPherson, P.S., and Hayden, M.R. (2001) HIP1 functions in clathrin-mediated endocytosis through binding to clathrin and AP2.听J. Biol. Chem.听276:39271-39276.
Hussain, N.K., Jenna, S., Glogauer, M., Quinn, C.C., Wasiak, S., Kay, B.K., Stossel, T.P., Lamarche-Vane, N., and听McPherson, P.S.听(2001) The endocytic protein intersectin-l regulates actin assembly via Cdc42 and N-WASP.听Nat. Cell Biol.听3:927-932.
Ramjaun, A.R., and听McPherson, P.S.听(1999) The N-terminus of amphiphysin II mediates dimerization and plasma membrane targeting.听J. Biol. Chem.听274:19785-19791.
Simpson, F.S., Hussain, N.K., Qualmann, B., Kay, B.K., Kelly, R.B.,听McPherson, P.S., and Schmid, S.L. (1999) SH3 domain-containing proteins function at distinct steps in clathrin-coated vesicle formation.听Nature Cell Biol.听1:119-124.
Hussain, N.K., Yamabhai, M., Ramjaun, A.R., Guy, A.M., Baranes, D., O'Bryan, J.P., Der, C.J., Kay, B.K., and听McPherson, P.S.听(1999) Splice variants of intersectin are components of the endocytic machinery in neurons and non-neuronal cells.听J. Biol. Chem.听274:15671-15677.