Email: peter.mcpherson [at] mcgill.ca (Peter McPherson)
Website: McPherson Lab
Recent Publications: PubMed, Google Scholar
Academic Affiliations: Neurology and Neurosurgery, Anatomy and Cell Biology
Research Groups: Neurodegenerative Diseases, Brain Tumour
Peter S. McPherson (PhD, FRSC), is a James McGill 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) 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.
Xu, J., Fotouhi, M., and McPherson, P.S. (2015) Phosphorylation of the exchange factor DENND3 by ULK in response to starvation activates Rab12 and induces autophagy. EMBO Reports 16: 709-718. (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 McPherson, P.S. (2015) DENND2B activates Rab13 at the leading edge of migrating cells and promotes metastatic behavior. J. Cell Biol. 208: 629-648. (Featured in a JCB Podcast called biobytes, in which the journal highlights one significant paper appearing in each issue. A 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. Featured in the Faculty of 1000).
Schreij, A.M.A., Chaineau, M., Ruan, W., Lin, S., Barker, P.A., Fon, E.A., and McPherson, P.S. (2015) LRRK2 functions in concert with clathrin-light chains to limit Rac1 activation and control actin cytoskeleton dynamics. EMBO Reports. 16: 79-86.
Hamlin, J.N.R., Schroeder, L., Fotouhi, M., Dokainish, H., Ioannou, M.S., Girard, M., Melançon, P., and McPherson, P.S. (2014) Scyl1 scaffolds class II Arfs to selective subcomplexes of coatomer through the gamma-COP appendage domain. J. Cell Sci. 127: 1454-1463 (Highlighted in the “In This Issue” feature of the Journal of Cell Science).
Vilariño-Güell, 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., McPherson, P.S., Girard, M., Rajput, M., Rajput, A.H., and Farrer, M.J. (2014) DNAJC13 mutations in Parkinson Disease. Hum. Mol. Genet. 23: 1794-1801.
Wu, Y., O’Toole, E.T., Girard, M., Ritter, B., Messa, M., Liu, X., 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. Elife 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 McPherson, P.S. (2013) NECAP 1 regulates AP-2 interactions to control vesicle size, number and cargo during clathrin-mediated endocytosis. PLoS Biology. 11: e1001670.
Allaire, P.D., Seyed Sadr, M., Chaineau, M., Seyed Sadr, E., Konefal, S., Maret, D., Fotouhi, M., Ritter, B. Del Maestro, R.F. and McPherson, P.S. (2013) Interplay between Rab35 and Arf6 controls cargo recycling to coordinate cell adhesion and migration. J. Cell Sci. 126: 722-731. (Highlighted in the “In This Issue” feature of the Journal of Cell Science).
Girard, M., Larivière, 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 McPherson, P.S. (2012) Mitochondrial dysfunction and Purkinje cell loss in Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS). Proc. Natl. Acad. Sci., USA 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 Nature News and Views, Narenda, D.P. and Youle, R.J. (2012) Neurodegeneration: Trouble in the cell's powerhouse, Nature, 483: 418-419).
Marat, A., Dokainish, H. and McPherson, P.S. (2011) DENN domain proteins: regulators of Rab GTPase J. Biol. Chem. 286: 13791-13800 (invited minireview)
Allaire, P.D., Marat, A.L., Dall'Armi, C., Di Paolo, G., McPherson, P.S.*, and Ritter, B*. (2010) The connecdenn DENN domain: A GEF for Rab35 mediating cargo-specific exit from early endosomes. Mol. Cell. 37: 370-382. *=co-corresponding author.
Katoh, Y., Ritter, B., Gaffry, T., Blondeau, F., Höning, S., and McPherson, P.S. (2009) The clavesin family: neuron-specific lipid- and clathrin-binding Sec14 proteins regulating lysosomal morphology. J. Biol. Chem. 284: 27646-27654.
Burman, J.L., Bourbonniere, L., Philie, J., Stroh, T., Dejgaard, S.Y., Presley, J.F. and McPherson, P.S. (2008) Scyl1, mutated in a recessive form of spinocerebellar neurodegeneration, regulates COPI-mediated retrograde traffic. J. Biol. Chem. 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 McPherson, P.S. (2008) Clathrin-light chains function in mannose phosphate receptor trafficking via regulation of actin assembly. Proc. Natl. Acad. Sci., USA, 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 McPherson, P.S. (2006) Connecdenn, a novel DENN domain-containing protein of neuronal clathrin-coated vesicles functioning in synaptic vesicle endocytosis J. Neurosci. 26:13,202-13,212.
Girard, M., Allaire, P.D., 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. Mol. Cell Proteomics. 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 McPherson, P.S. (2004) Tandem mass spectrometry analysis of brain clathrin-coated vesicles reveals their critical involvement in synaptic vesicle recycling. Proc. Natl. Acad. Sci., USA 101:3833-3838. (selected by the Faculty of 1000)
Ritter, B., Philie, J., Girard, M., Tung, E.C., Blondeau, F., and McPherson, P.S. (2003) Identification of a family of endocytic proteins that define a new alpha-adaptin ear-binding motif. EMBO Reports 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 McPherson, P.S. (2002) Enthoprotin, a novel clathrin-associated protein identified through subcellular proteomics. J. Cell Biol.158:855-862.
Metzler, M., Legendre-Guillemin, V., Gan, L., Chopra, V., Kwok, A., McPherson, P.S., and Hayden, M.R. (2001) HIP1 functions in clathrin-mediated endocytosis through binding to clathrin and AP2. J. Biol. Chem. 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 McPherson, P.S. (2001) The endocytic protein intersectin-l regulates actin assembly via Cdc42 and N-WASP. Nat. Cell Biol. 3:927-932.
Ramjaun, A.R., and McPherson, P.S. (1999) The N-terminus of amphiphysin II mediates dimerization and plasma membrane targeting. J. Biol. Chem. 274:19785-19791.
Simpson, F.S., Hussain, N.K., Qualmann, B., Kay, B.K., Kelly, R.B., McPherson, P.S., and Schmid, S.L. (1999) SH3 domain-containing proteins function at distinct steps in clathrin-coated vesicle formation. Nature Cell Biol. 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 McPherson, P.S. (1999) Splice variants of intersectin are components of the endocytic machinery in neurons and non-neuronal cells. J. Biol. Chem. 274:15671-15677.
de Heuvel, E., Bell, A.W., Ramjaun, A.R., Wong, K., Sossin, W.S., and McPherson, P.S. (1997) Identification of the major synaptojanin-binding proteins in brain. J. Biol. Chem. 272:8710-8716.