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	Yale University School of Medicine CNNR Program
	P.O. Box 9812 New Haven, CT 06536-9812
	(203) 785-4736 Tel. (203) 785-5098 Fax

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		Pietro De Camilli, M.D.
		Eugene Higgins Professor of Cell Biology and Neurobiology Investigator, Howard Hughes Medical Institute Director, Yale Program in Cellular Neuroscience, Neurodegeneration and Repair Member, Yale Kavli Neuroscience Institute
		Yale University School of Medicine Dept. of Cell Biology 295 Congress Ave. BCMM 236 New Haven, CT 06519
		Phone: 203.737.4461 Fax: 203.737.4436 Email: pietro.decamilli@yale.edu

Dr. De Camilli received his M.D. degree from the University of Milano, and a postgraduate degree in Endocrinology from the University of Pavia, Italy. He became interested in neurobiology during his postdoctoral studies at Yale University in Paul Greengard' s laboratory, prior to being recruited as a faculty member to the Yale Section of Cell Biology by George Palade. Following a return of a few years to Milano, he moved back permanently to Yale in the late 1980s. From 1997 to 2000 he served as the Chair of the Deparment of Cell Biology and in 2005 he was the co-founder of the Yale Program in Cellular Neuroscience, Neurodegeneration and Repair. Dr. De Camilli is a member of the National Academy of Sciences, the American Academy of Arts and Sciences and the Instiute of Medicine. He is also a member of the European Molecular Biology Organization.

Research Abstract

We study the mechanisms underlying the development and function of neuronal synapses and the role of abnormal synaptic function in neurological and psychiatric diseases, including neurodegenerative diseases. Synapses are specialized contact sites between neurons, or between neurons and muscle, where electrical signals are propagated from cell to cell via chemical intermediates called neurotransmitters. Our long-term goal is to advance the understanding of nervous system function in health and disease. In addition, we also exploit the unique structural and functional features of synapses to learn about general principles in cells biology.

A main focus of our research is the elucidation of the mechanisms responsible for the biogenesis and traffic of synaptic vesicles, the secretory organelles that store and secrete fast-acting neurotransmitters. Synaptic vesicles deliver their content into the synaptic space by fusion with the plasma membrane (exocytosis) and are rapidly reformed by the endocytosis and recycling of their membranes. Thus, studies of these organelles have general relevance for the understanding of mechanisms involved in the secretory and endocytic pathways in all cells. Current projects address 1) the clathrin-dependent internalization of synaptic vesicles, 2) the mechanisms underlying acquisition of membrane curvature and vesicle fission, 3) the biochemical steps involved in the transformation of an uncoated clathrin coated vesicle into a mature synaptic vesicle, 4) the role of the cortical cytoskeleton in regulating synaptic vesicle traffic to and from the plasma membrane. We are particularly interested in the role of protein-lipid interactions in vesicle traffic. These studies have led us to discover an important function of inositol phospholipids (phosphoinositides) in synaptic vesicle recycling. We are actively pursuing studies on the regulatory function of these phospholipids in brain and other selected organs.

Links

HHMI Research News - "Reconsidering Dynamin's Role in Nerve Cell
Function"

Selected Publications

Volpicelli-Daley L, and De Camilli P. Phosphoinositides' link to neurodegeneration. 2007. Nat. Med. 13: 784-786.

Di Paolo G, and De Camilli P. 2006. Phosphoinositides in cell regulation and membrane dynamics. Nature. 443: 651-657

Roux A, Uyhazi K, Frost A, and De Camilli P. 2006. GTP-dependent twisting of dynamin implicates both constriction and tension in membrane fission. Nature. 441: 528-531.

Ferguson SM, Brasnjo G, Hayashi M, Wölfel M, Collesi C, Giovedi S, Raimondi A, Gong LW, Paradise S, O’Toole E, Flavell R, Cremona O, Miesenböck, Ryan TA, and De Camilli P. 2006. Synaptic vesicle recycling requires dynamin 1 only during sustained stimulation. Science. 316: 570-574 .

Erdmann KS, Mao Y, McCrea H, Lee S, Zoncu R, Paradise S, Modregger J, Biemesderfer D, Toomre D, and De Camilli, P. 2007. A role of the Lowe syndrome protein OCRL in early steps of the endocytic pathway. Dev. Cell. 13: 377-390.

Frost A, Roux A, Perera R, Spasov K, Destaing O, Egelman EH, De Camilli P, and Unger VM. 2008. Structural basis of membrane invagination by F-Bar domains. Cell. 132:807-817.

Selected bibliography

De Camilli P, Harris SM, Huttner WB, and Greengard P. 1983. Synapsin I (Protein I), a nerve terminal-specific phosphoprotein: II. Its specific association with synaptic vesicles demonstrated by immunocytochemistry in agarose-embedded synaptosomes. J. Cell Biol. 96: 1355-1373.

Huttner WB, Schiebler W, Greengard P, and De Camilli P. 1983. Synapsin I (Protein I), a nerve terminal-specific phosphoprotein: III. Its association with synaptic vesicles studied in a highly-purified synaptic vesicle preparation. J. Cell Biol. 96: 1374-1388.

Navone F, Greengard P, and De Camilli P. 1984. Synapsin I in nerve terminals: selective association with small synaptic vesicles. Science. 226: 1209-1211.

Solimena M, Folli F, Aparisi R, Pozza G, and De Camilli,P. 1990. Autoantibodies to GABA-ergic neurons and pancreatic ß-cells in Stiff-Man Syndrome: a study of 33 cases. New Engl. J. Med. 322: 1555-1560.

Baekkeskov S, Aanstoot HJ, Christgau S, Reetz A, Solimena M, Cascalho M, Folli F, Richter-Olesen H, and De Camilli P. 1990. The 64kD autoantigen in insulin-dependent diabetes is the GABA synthesizing enzyme glutamic acid decarboxylase. Nature. 347: 151-156.

Folli F, Solimena M, Cofiell R, Austoni M, Tallini G, Fassetta G, Bates D, Cartlidge N, Bottazzo GF, Piccolo G, and De Camilli P. 1993. Autoantibodies to a 128kD synaptic protein in three women with the Stiff-man syndrome and breast cancer. New Engl. J. Med. 328: 546-551.

Takei K, McPherson P, Schmid SL, and De Camilli P. 1995. Tubular membrane invaginations coated in dynamin rings are induced by GTP-gs in nerve terminals. Nature. 374: 186-190.

McPherson PS, Garcia EP, Slepnev V, David C, Zhang X, Grabs D, Sossin WS, Bauerfeind R, Nemoto Y, and De Camilli P. 1996. A presynaptic inositol-5-phosphatase. Nature. 379: 353-357.

De Camilli P, Emr SD, McPherson PS, and Novick P. 1996. Phosphoinositides as regulators in membrane traffic. Science. 271: 1533-1539.

Shupliakov O, Löw P, Grabs D, Gad H, Chen H, David C, De Camilli P, and Brodin L. 1997. Synaptic vesicle endocytosis impaired by disruption of dynamin-SH3 domain interactions. Science. 276: 259-263.

Takei K, Haucke V, Slepnev V, Farsad K, Salazar M, Chen H, and De Camilli P. 1998. Generation of coated intermediates of clathrin-mediated endocytosis on protein-free liposomes. Cell. 94: 131-141.

Chen H, Fre S, Slepnev VI, Capua MR, Takei K, Butler MH, Di Fiore PP and De Camilli P. 1998. Epsin, an EH domain binding protein implicated in clathrin-mediated endocytosis. Nature. 394: 793-797.

Slepnev V, Ochoa GC, Butler MH, Grabs D, and De Camilli P. 1998. Role of phosphorylation in the regulation of the assembly of endocytic coat complexes. Science. 281: 821-824.

Takei K, Slepnev VI, Haucke V, and De Camilli P. 1999. Functional partnership between amphiphysin and dynamin in clathrin-mediated endocytosis. Nat. Cell Biol. 1: 33-39.

Haucke V, and De Camilli P. 1999. AP-2 recruitment to synaptotagmin stimulated by tyrosine-based endocytic motifs. Science. 285: 1268-1271.

Cremona O, Di Paolo G, Wenk M, Luthi A, Kim WT, Takei K, Daniell L, Nemoto Y, Flavell RA, McCormick DA and De Camilli P. 1999. Essential role of phosphoinositide metabolism in synaptic vesicle recycling. Cell. 99: 179-188.

Gad H, Ringstad N, Löw P, Kjaerulff O, Gustafsson J, Wenk M, DiPaolo G, Nemoto Y, Crum J, Ellisman MH, De Camilli P, Shupliakov O, and Brodin L. 2000. Fission and uncoating of clathrin-coated vesicles at the synapse is perturbed by disruption of interactions with the SH3 domain of endophilin. Neuron. 27: 301

Chang S, and De Camilli P. 2001. Glutamate-mediated regulation of actin-based in axonal filopodia. Nat. Neurosci. 8: 787-793.

Wenk MR, Pellegrini L, Klenchin VA, Di Paolo, G, Chang S, Daniell L, Arioka M, Martin TF, and De Camilli P. 2001. PIP kinase Iγ is the major PI(4,5)P2 synthesizing enzyme at the synapse. Neuron . 32: 79-88.

Farsad K, Ringstad N, Takei K, Floyd SR, and De Camilli P. Generation of high curvature membranes mediated by direct endophilin-bilayer interactions. 2001. J. Cell Biol. 155: 193-200.

Polo S, Bossi G, Sigismund S, Feretta M, Guidi M, Capuo MR, Bossi G, Chen H, De Camilli P, and Di Fiore PP. 2002. A single motif responsible for ubiquitin recognition and monoubiquitation in endocytic proteins. Nature. 416: 451-455.

Lee E, Marcucci M, Daniell L, Pypaert M, Weisz OA, Ochoa GC, Farsad K, Wenk MR, and De Camilli P. 2002. Amphiphysin 2 (Bin1) and T-tubule biogenesis in muscle. Science.297: 1193-1196.

Di Paolo G, Pellegrini L, Letinic K, Voronov S, Chang S, Wenk MR, and De Camilli P. 2002. Recruitment and regulation of PIP kinase type 1γ by the FERM domain of talin. Nature. 420: 88-89.

Wenk MR, Lucast L, Di Paolo G, Romanelli AJ, Suchy SF, Nussbaum RL, Cline GW, McMurray W, and De Camilli P. 2003. Phosphoinositide profiling in complex lipid mixtures using electrospray ionization mass spectrometry. Nat. Biotechnol. 21: 813-817.

Chen H, Polo S, Di Fiore PP, and De Camilli P. 2003. Rapid Ca2+-dependent decrease of protein ubiquitination at synapses. Proc. Nat. Acad. Sci. 100: 14908-14913.

Wenk MR, and De Camilli P. 2004. Protein-lipid interactions and phosphoinositide metabolism in membrane traffic: insights from vesicle recycling in nerve terminals. Proc. Nat. Acad. Sci. 101: 8262-8269.

Di Paolo G, Moskowitz HS, Gipson K, Wenk MR, Voronov S, Obayashi M, Flavell R, Fitzsimonds RM, Ryan TA, and De Camilli P. 2004. Impaired PI(4,5)P2 synthesis in nerve terminals produces synaptic vesicle trafficking defects. Nature. 431: 415-422.

Morgan JR, Di Paolo G. Werner H, Schedrina VA, Pypaert M, Pieribone V, and De Camilli P. 2004. A role for talin in presynaptic function. J. Cell Biol. 167: 43-50.

Lee SY, Voronov S, Letinic K, Nairn AC, Di Paolo G, and De Camilli P. 2005. Regulation of the interaction between PIPKIγ and talin by proline-directed protein kinases. J. Cell Biol. 168: 789-799.

Gong LW, Di Paolo G, Diaz E, Lindau M, De Camilli P, and Toomre D. 2005. PIP kinase type Ig regulates dynamics of large dense-core vesicle fusion. Proc. Nat. Acad. Sci. 102: 5204-5209.

Shin HW, Hayashi M, Christoforidis S, Lacas-Gervais S, Wenk M, Modregger J, Uttenweiler-Joseph S, Wilm M, Nystuen A, Frankel WN, Solimena M, De Camilli P, and Zerial M. 2005. An enzymatic cascade of rab5 effectors regulates phosphoinositide turnover in the endocytic pathway. J. Cell Biol. 170: 607-618.

Mao Y, Senic-Matuglia F, Di Fiore PP, Polo S, Hodsdon ME, and De Camilli P 2005. De-ubiquintinating function of ataxin-3: insights from the solution structure of the Josephin domain. Proc. Nat. Acad. Sci. 102: 12700-12705.

Itoh T, Erdmann KS, Roux A, Habermann B, Werner H, and De Camilli P. 2005. Dynamin and the actin cytoskeleton cooperatively regulate plasma membrane invagination by BAR and F-BAR proteins. Dev. Cell. 6: 791-804.

Perera RM, Zoncu R, Lucast L, De Camilli P, and Toomre D. 2006. Two synaptojanin 1 isoforms are recruited to clathrin coated pits at different stages. Proc. Nat. Acad. Sci. 103: 19332-19337.

Zoncu R, Perera RM, Sebastian R, Nakatsu F, Chen H, Balla T, Ayala G, Toomre D, and De Camilli P. 2007. Loss of endocytic clathrin coated pits upon acute depletion of phosphatidylinositol 4,5 bisphosphate. Proc. Nat. Acad. Sci. 103: 19332-19337.

Frost A, De Camilli P, and Unger VM. F-BAR proteins join the BAR family fold. 2007. Structure. 15: 751-753.

Gil-Henn H, Destaing O, Sims NA, Aoki K, Alles N, Neff L, Sanjay A, Bruzzaniti A, De Camilli P, Baron R, and Schlessinger J. 2007. Defective microtubule-dependent podosome organization in osteoclasts leads to increased bone density in Pyk2-/- Mice. J. Cell Biol. 178: 1053-1064.

Mani M, Lee SY, Lucast L, Cremona O, Di Paolo G, De Camilli P, and Ryan TA. 2007. The dual phosphatase activity of snyaptojanin is required for both efficient synaptic vesicle internalization and re-availability at nerve terminals. Neuron. 56: 1004-10018.

Hayashi M, Raimondi A, O’Toole E, Paradise S, Collesi C, Cremona O, Ferguson SM, and De Camilli P. 2008. Cell and stimulus dependent heterogeneity of synaptic vesicle endocytic recycling revealed by studies of dynamin 1-null neurons. Proc. Nat. Acad. Sci. 105: 2175-2180.

McCrea HJ, Paradise S, Tomasini L, Addis M, Melis MA, De Matteis MA and De Camilli P. 2008. All known patient mutations in the ASH-RhoGAP domains of OCRL affect targeting and APPL1 binding. Biochem Biophys Res Commun. 369:493-499.

Frost A, Unger VM and De Camilli P. 2008. Boomerangs, Bananas and Blimps: Structure and Function of F‑BAR Domains in the Context of the BAR Domain Superfamily. In “The Pombe Cdc15 Homology Proteins”, Aspenström P ed. Landes Bioscience.

Voronov SV, Frere SG, Giovedi S, Pollina EA, Borel C, Zhang H, Schmidt C, Akeson EC, Wenk MR, Cimasoni L, Arancio O, Antonarakis SE, Davisson MT, Antonarakis SE, Gardiner K, De Camilli P, and Di Paolo G. 2008. Synaptojanin 1-linked phosphoinositide dyshomeostasis and cognitive deficits in mouse models of down syndrome. Proc. Nat. Acad. Sci. 105: 9415-9420.

Krauss M, Jia JY, Roux A, Beck R, Wieland FT, De Camilli P, and Hauke V. 2008. Arf1-GTP-induced tubule formation suggests a function of Arf family proteins in curvature acquisition at sites of vesicle budding. J. Biol. Chem. 283: 27717-27723.

Gong LW, and De Camilli P. 2008. Regulation of postsynaptic AMPA responses by synaptojanin I. In Press. Proc. Nat. Acad. Sci. 105: 17561–17566

Lou X, Paradise S, Ferguson SM, De Camilli P. 2008. Selective saturation of slow endocytosis at a giant glutamatergic central synapse lacking dynamin 1. In Press. Proc. Nat. Acad. Sci. 105: 17555–17560

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