Peter Scott McPherson, PhD
Le Dr. Peter McPherson, Ph. D., MSRC, est professeur de neurologie et de neurochirurgie, ainsi que d鈥檃natomie et de biologie cellulaire 脿 l鈥橧nstitut neurologique de Montr茅al (Neuro) de l鈥橴niversit茅 平特五不中. Il est titulaire d鈥檜ne chaire James 平特五不中 de l鈥橴niversit茅 平特五不中 et fait partie du Groupe de recherche sur les maladies neurod茅g茅n茅ratives du Neuro.听
Le laboratoire de Peter S. McPherson se sert d'approches biochimiques, mol茅culaires, structurales, g茅n茅tiques et cellulaires pour identifier et effectuer la caract茅risation fonctionnelle des prot茅ines qui interviennent dans la formation des v茅sicules 脿 manteau de clathrine. Celles-ci sont les principaux v茅hicules de l鈥檃bsorption endocytique de multiples charges prot茅iques et lipidiques, dont des nutriments et des r茅cepteurs de signalisation. Apr猫s l鈥檈ndocytose, la charge est livr茅e aux endosomes d鈥檕霉 elle est recycl茅e vers la surface cellulaire ou dirig茅e vers les lysosomes aux fins de d茅gradation. Ces d茅cisions de tri contr么lent la localisation et les niveaux de prot茅ines et sont alt茅r茅es dans le cancer et la maladie neurologique. Ainsi, des projets en cours au laboratoire r茅v猫lent comment un d茅r猫glement dans le transport de charges s茅lectives des endosomes 脿 la surface cellulaire contribue au d茅veloppement de glioblastome et du cancer du sein.
Auparavant, le laboratoire du Pr听McPherson a eu recours 脿 la prot茅omique subcellulaire (fractionnement subcellulaire et spectrom茅trie de masse 脿 haut d茅bit) pour identifier le compl茅ment int茅gral de prot茅ines qui caract茅risent les v茅sicules 脿 manteau de clathrine de plusieurs tissus. Parmi les prot茅ines identifi茅es figurent certaines qui n鈥櫭﹖aient connues que sous forme de cadres ouverts de lecture non caract茅ris茅s. Le laboratoire du PrMcPherson a caract茅ris茅 la fonction de certaines des nouvelles prot茅ines, mais il en reste un nombre important 脿 茅tudier. Une prot茅ine r茅cemment identifi茅e contient un module appel茅 un domaine DENN. Le Pr听McPherson et ses coll猫gues ont d茅montr茅 que les domaines DENN fonctionnent de fa莽on enzymatique comme un facteur d鈥櫭ヽhange du nucl茅otide de la guanine pour activer de petites GTPases de la famille Rab. Le g茅nome humain compte au minimum 26听prot茅ines 脿 domaine DENN et un champ important d鈥櫭﹖udes au laboratoire porte sur la relation de ces prot茅ines avec les ~70 Rab fonctionnant dans le trafic membranaire. Un exemple particuli猫rement frappant est la prot茅ine 脿 domaine DENN C9orf72, dont la fonction est inconnue. Une mutation dans C9orf72 est la cause la plus fr茅quente de formes g茅n茅tiques de scl茅rose lat茅rale amyotrophique (SLA) et le laboratoire cherche 脿 comprendre la relation entre le trafic des membranes endosomiques et la pathogen猫se de la maladie.
Certaines prot茅ines identifi茅es ou 茅tudi茅es au laboratoire du Pr听McPherson ont 茅t茅 associ茅es 脿 des maladies neurologiques comme la maladie de Huntington, l鈥檃taxie spastique r茅cessive autosomique de Charlevoix-Saguenay (ARSACS) et la maladie de Parkinson (MP). Par exemple, nous avons d茅montr茅 que le LRRK2, g猫ne majeur de la MP, se lie aux clathrines et fonctionne dans le trafic des membranes endosomiques. De plus, nous avons montr茅 que l鈥橝RSACS a la m锚me physiopathologie que la MP. En fait, des alt茅rations dans la r茅gulation du transport membranaire 茅mergent comme un th猫me central des maladies neurod茅g茅n茅ratives. Comprendre le fondement biologique cellulaire de la maladie neurologique est un nouveau champ d鈥檌nt茅r锚t du laboratoire.
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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)
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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).
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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.
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Hamlin, J.N.R., Schroeder, L., Fotouhi, M., Dokainish, H., Ioannou, M.S., Girard, M., Melan莽on, 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 鈥淚n This Issue鈥� feature of the Journal of Cell Science).
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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., 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.
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Wu, Y., O鈥橳oole, 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.
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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.
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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 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 鈥淚n This Issue鈥� feature of the Journal of Cell Science).
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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 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).
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Marat, A., Dokainish, H. and McPherson, P.S. (2011) DENN domain proteins: regulators of Rab GTPase J. Biol. Chem. 286: 13791-13800 (invited minireview)
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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.
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Katoh, Y., Ritter, B., Gaffry, T., Blondeau, F., H枚ning, 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.
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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)
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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)
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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.
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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.
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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)
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
