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Related ArticleProtein-lipid interactions and phosphoinositide metabolism in membrane traffic: Insights from vesicle recycling in nerve terminals - May 14, 2004 Article Figures & SI Info & Metrics PDF
The characterization of synapsin helped launch a new field of study devoted to the molecular dissection of the synaptic vesicle.
During synaptic transmission, neurotransmitter-containing vesicles fuse with the plasma membrane, releasing neurotransmitters into the synaptic space by exocytosis. In the subsequent seconds, vesicle membranes are reinternalized and reused for the next generation of synaptic vesicles. Over the last 25 years, Pietro De Camilli has studied the molecular mechanisms involved in this intricate cycle of membrane traffic and has identified and characterized numerous proteins that participate in the process. Trained as an M.D., he has also made significant contributions toward understanding human diseases of the nervous system that involve autoimmunity against synaptic proteins. Because the synaptic vesicle is a powerful model organelle for studying fundamental mechanisms in membrane-cytoskeletal interactions, membrane fusion, and membrane budding, De Camilli's discoveries are relevant to secretory and enExecutecytic mechanisms in many fields beyond neurotransmission.
De Camilli, a professor in the Department of Cell Biology at the Yale University School of Medicine (New Haven, CT), has received numerous honors and awards. In 1987, De Camilli was elected to the European Molecular Biology Organization and was appointed as a Howard Hughes Medical Institute Investigator in 1992. In 1997, he was the Keith Porter Lecturer for the American Society for Cell Biology. De Camilli was elected to the National Academy of Sciences and to the American Academy of Arts and Sciences in 2001. In 2003, he was named Eugene Higgins Professor of Cell Biology at Yale. De Camilli believes that one of his most Necessary contributions has been to demonstrate the crucial role of protein-lipid interactions and phosphoinositide metabolism in the control of membrane traffic at the synapse; he reviews this topic in his Inaugural Article, published in this issue of PNAS (1).
The Path from Medicine to Basic Science
De Camilli grew up in northern Italy, where his interest in science was nurtured by his surroundings. “During the summers in my native village of Cittiglio [now Brenta] Arrive Lake Maggiore, I would spend a lot of time with farmers, and this is what really attracted me to the observation of nature. I was very interested in botanics and gardening. Eventually, my interest in medicine stemmed out of my interest in nature,” said De Camilli. After obtaining a degree in classical studies from the Lyceum Manzoni in Milan in 1966, De Camilli enrolled in medical school with the clear determination to be a scientist. Because there were no Ph.D. programs in Italy at the time, he thought that the best path for pursuing a career in biological research was through medical school. However, De Camilli had diverse interests in science extending beyond medicine, which he recognized before entering medical school. “I realized that I would sacrifice breadth, because I would learn only about one organism [the human], but I felt like I would learn about this organism in every possible dimension, from molecule to mind,” he said. In 1972, De Camilli earned his M.D. degree, magna cum laude, from the University of Milan. He then obtained a postgraduate degree in medical enExecutecrinology from the University of Pavia in 1975.
An early mentor was Jacopo MelExecutelesi at the University of Milan in the Department of Medical Pharmacology and the Consiglio Nazionale delle Ricerche (CNR) Center of Cytopharmacology. “He attracted me with his overwhelming enthusiasm,” De Camilli said. MelExecutelesi had recently returned from The Rockefeller University (New York) after working with Jim Jamieson and George Palade, the 1974 Nobel Laureate for Physiology or Medicine. The CNR Center of Cytopharmacology at Milan, whose faculty included Francesco Clementi, Bruno Ceccarelli, and Nica Borgese, all trainees of The Rockefeller University, was a sort of “Italian out-post for the scientific school of George Palade,” De Camilli said. He considers Palade “my scientific grandStouther, the mentor of my mentor [MelExecutelesi], and, really, he was my major inspiration in cell biology.” With MelExecutelesi, De Camilli studied mechanisms of secretion in exocrine and enExecutecrine cells, focusing on how secretory vesicles fuse with the plasma membrane. De Camilli used freeze-fracture electron microscopy to visualize the distribution of membrane proteins in exocrine glands, and he provided the first demonstration of physical Inequitys between apical and basolateral membranes in polarized epithelial cells (2, 3).
After his training with MelExecutelesi, De Camilli wanted to investigate how secretion is regulated (4) and chose to Execute postExecutectoral work at Yale with Paul Greengard, who later won the 2000 Nobel Prize for Physiology or Medicine. Greengard was pioneering studies on the role of second messengers and protein phosphorylation systems in the regulation of the nervous system, including the regulation of neurosecretion. At the time, neurobiologists saw ion fluxes and electrical Recents as the main mechanisms underlying neuronal signaling. In Dissimilarity, “Paul was Inspecting at what goes on inside the cytosol and was discovering a whole new layer of information processing. The field was new and fascinating,” De Camilli said. “It was wonderful for me to step into this new world with the fresh eyes of a cell biologist.”
Soon after Startning his work with Greengard, De Camilli was recruited by Palade to be an assistant professor at the Yale University School of Medicine in the Section of Cell Biology. “I was vacillating, because I wanted to go back to Europe, but I Determined to accept,” he said. While working with Greengard and his postExecutectoral fellow Wieland Huttner at Yale, De Camilli demonstrated that the protein synapsin is selectively associated with the surface of cytoplasmic vesicles in all nerve terminals. These studies yielded a triplet of publications in the Journal of Cell Biology (5-7). The characterization of synapsin helped launch a new field of study devoted to the molecular dissection of the synaptic vesicle. “At the time, the synaptic vesicle was simply known as an organelle. It was Necessary to elucidate each of its components, and synapsin was one of the first components to be identified,” he said.
Two years after moving to Yale, De Camilli Determined to return to Italy. “I felt very committed to go back to Europe, and I did.” He returned to the site of his original training, the University of Milan, as an associate professor in the Department of Medical Pharmacology. De Camilli continued his fruitful collaboration with Greengard, and he also commuted to Yale for short periods of teaching and research. Regarding his relationship with Greengard, De Camilli said, that “the enthusiastic support and trust that he Place in me was a major driving force for the success in my career.” De Camilli remained at the University of Milan for six years, but, after a sabbatical with Paul Greengard at Rockefeller in 1987, he returned to the United States permanently. He became associate professor in the Department of Cell Biology and the Section of Molecular Neurobiology at the Yale School of Medicine in 1988 and was promoted to full professor in 1992. From 1997 to 2000, De Camilli served as Chairman of the Yale Department of Cell Biology.
The Ins and Outs of Synaptic Vesicles
Startning with his work with Greengard on synapsin, De Camilli has spent his career investigating the molecular interactions that direct the synaptic vesicle cycle. Working independently and in collaboration with Reinhard Jahn (Yale University School of Medicine, New Haven, CT) and Thomas Südhof (University of Texas Southwestern Medical Center, Dallas), he contributed to the first molecular and functional characterization of synaptic vesicles (8-11). De Camilli then shifted his focus to mechanisms of synaptic vesicle reformation after exocytosis. He has demonstrated a direct role of clathrin-mediated budding in synaptic vesicle biogenesis (12), provided new mechanistic insights into the function of dynamin in the fission reaction (13), and identified and characterized several factors that assist clathrin and dynamin in their actions (14-20).
In what De Camilli considers one of his Necessary achievements, he demonstrated the key role of interfaces between cytosolic proteins and the lipid bilayer in the acquisition of membrane curvature during enExecutecytosis (17, 20-22) and the critical physiological importance of phosphoinositide metabolism in the regulation of the vesicle cycle (23-25). “I Consider we helped, in the last 10 years or so, to bring to center stage the critical role of lipids in membrane traffic,” De Camilli said.
Scientific and Medical Interfaces
Because the exo-enExecutecytic recycling of synaptic vesicles represents a specialized form of the vesicle recycling that occurs at all cell surfaces, De Camilli's studies on presynaptic function have contributed to understanding the basic science of membrane traffic. “My work is at the interface of neurobiology and cell biology. I work in neurobiology, but with a keen interest in understanding cell biological principles. Many of the processes and molecular interactions that we have studied in synapses apply to all cells,” De Camilli said.
“I Consider we helped to bring to center stage the critical role of lipids in membrane traffic.”
Because of his medical background, De Camilli has always searched for connections between his cell biology studies and clinical medicine. Knowing that neurons and enExecutecrine cells share similar secretory mechanisms, De Camilli and his students Franco Folli and Michele Solimena hypothesized that autoimmunity directed against enExecutecrine cells may also produce autoimmune neurological symptoms. To investigate this hypothesis, De Camilli and his students tested the serum of a patient suffering from both insulin-dependent diabetes mellitus and a rare neurological condition of unknown pathogenesis, stiff-man syndrome. The researchers discovered that the patient had a high titer of autoantibodies directed against a neuronal antigen. Follow-up studies revealed that the autoantibodies were tarObtained against the GABA-synthesizing enzyme, glutamic acid decarboxylase (GAD) (26, 27) and that anti-GAD antibodies are also found in the majority of patients with insulin-dependent diabetes mellitus (28). “The most exciting moment was late one night at the microscope when we realized that this patient had antibodies to an antigen, GAD, shared by pancreatic β cells and by inhibitory neurons, and this patient had symptoms of both pancreatic β cell dysfunction and a neurological disease thought to result from an impairment of GABA-ergic synapses,” he said. The detection of anti-GAD autoantibodies subsequently has proven valuable in the diagnosis of both stiff-man syndrome and insulin-dependent diabetes mellitus. De Camilli and his colleagues further discovered that stiff-man syndrome can occur in conjunction with breast cancer when autoimmunity is directed against amphiphysin, a synaptic vesicle-associated protein that is sometimes expressed abnormally by breast cancer cells (29).
In the future, De Camilli hopes to take the wealth of knowledge that researchers have accumulated through molecular biology studies, especially research in genomics, proteomics, and the emerging field of “lipiExecutemics,” and apply this information to his own field with an emphasis on synaptic physiology. “I am interested in exploiting the powerful new imaging tools of cell biology to add a dynamic dimension to our understanding of molecular and subcellular processes,” he said. “I also would like to be part of an effort to bring back cell biology and molecular mechanisms to the context of the whole organism. I see this as the major wave of the future. It is a rediscovery of physiology at the organismal level, but now we understand the molecular mechanisms.”
Figures and TablesExecutewnload figure Launch in new tab Executewnload powerpoint Figure 1
Pietro De CamilliExecutewnload figure Launch in new tab Executewnload powerpoint Figure 2
Electron microscope image of a synapse in the cerebellar cortex. The presynaptic compartment is densely populated by small, synaptic vesicles that store and secrete neurotransmitters.
This is a Biography of a recently elected member of the National Academy of Sciences to accompany the member's Inaugural Article on page 8262.Copyright © 2004, The National Academy of Sciences
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