Südhof , Thomas

Thomas C. Südhof lay the foundations for his scientific career studying the synapse early while studying the mechanisms of neurotransmitter dependent hormone release from neuroendocrine cells for his doctoral thesis at the Max Planck Institute for Biophysical Chemistry. Südhof described the structure and function of chromaffin cells which are responsible for the release of epinephrine, norepinephrine, and endorphins from the medulla of the adrenal gland. Innervated by sympathetic nervous system, chromaffin cells are important in the initiation of the fight or flight response of animals when exposed to threatening stimuli.

After completing his thesis in 1983, Südhof moved to UT Southwestern Medical Center for his postdoctoral training where he began researching in the department of molecular genetics under the supervision of Joseph L. Goldstein and Michael Stuart Brown. While a postdoctoral fellow, Südhof cloned the gene for the low-density lipoprotein receptor and, soon after, was able to explain its transcriptional regulation by cholesterol. When LDL receptors, found concentrated in the liver, bind specific free blood cholesterol, low-density lipoprotein, they are internalized and recycled removing the cholesterol from circulation. This process is a primary source of blood cholesterol regulation and variations in its efficiency were shown to be present in familial hypercholesterolemia. As a result of the discovery, LDL receptor function had also elucidated the principle of receptor-mediated endocytosis—a now universally understood process in cell biology. Goldstein and Brown won the Nobel Prize in Physiology or Medicine for the discovery in 1985.

After finishing postdoctoral training, Thomas Südhof started his own laboratory at UT Southwestern in 1986. Briefly continuing work with Goldstein and Brown, Südhof helped identify a DNA element in the LDL gene that produced sterol mediated end-product repression when inserted in a viral promoter. This domain, known as a sterol regulatory sequence, directly participates in the regulation of sterol biosynthesis. Sterols are a major class of biomolecule and critical for life. Important sterols in humans include cholesterol and steroid hormones. Discovery of sterol regulatory elements and LDL receptor function led to the subsequent development of statin derived cholesterol medications such as atorvastatin (Lipitor)—the top-selling branded pharmaceutical drug in the world in 2008.

As he began working independently, what made Südhof’s research so unique was his focus on the presynaptic neuron. Until Südhof began his work, majority of neuroscience research was aimed at the postsynaptic neuron and its role in learning and memory. Indeed, Thomas Südhof is credited with discovering much of the machinery mediating neurotransmitter release and presynaptic pasticity in his 21 years at UT Southwestern. Südhof began with the discovery of synaptotagmins and their role in neurotransmitter release from the presynaptic neuron. Synaptotagmin, a transmembrane protein found in neurosecretory vesicles, functions as a calcium sensor triggering vesicle fusion and neurotransmitter release. Stimulation of a neuron results in an increase in intracellular calcium concentration. After binding calcium ion to a region in its cytosolic domain, vesicular synaptotagmin promotes quick or slow neurotransmitter release from the presynaptic neuron via interaction with regulatory and fusion related proteins such as members of the SNARE complex. Südhof also discovered RIMs and Muncs (most notably Munc13 and Munc18), soluble proteins which aid in the fusion of neurotransmitter vesicles to the nerve cell membrane and play an important role in synaptic plasticity. In addition, Südhof’s research uncovered the role of many other proteins facilitating vesicle binding, fusion, and resultant neurotransmitter release from the presynaptic neuron, including members of the SNARE complex: synaptobrevin, in the vesicular membrane, syntaxin, in the cell membrane, and SNAP-25, which is tethered to the cytosolic side of the cell membrane via cysteine-linked palmitoyl chains and holds the complex of four helices together. Südhof was also responsible for elucidating the action of tetanus and botulinum toxins, which selectively cleave synaptobrevin and SNAP-25, respectively, inhibiting vesicle fusion with the presynaptic membrane.

More recently, Thomas Südhof’s work has focused on aspects of synaptogenesis and maintenance of the synaptic connection. Südhof discovered neurexins, present on presynaptic neurons, and neuroligins, present on postsynaptic neurons, that come together to form a physical protein bridge across the synapse. The diversity in types of neurexins and neuroligins allows for a variety of unique binding opportunities between neurons and impart a specificity to synaptic connections. In additional studies, Südhof identified mutations in these proteins as a factor in inherited autism.

Thomas Südhof currently continues work on the presynaptic neuron and related topics in his laboratory at Stanford University. Yet to be determined is the mechanism by which neurexins and neuroligins locate each other to form the synapse, their transcriptional regulation, and control of their variability. Südhof’s research has not only given the scientific community a great understanding of the processes underlying synaptic transmission, but has also advanced medical knowledge of mechanisms behind poorly understood diseases such as Alzheimer’s, Schizophrenia, and Autism. He is currently working with a diverse group of researchers at the Howard Hughes Medical Institute to develop mouse models for mutants of synaptic genes. The project aims to drastically advance our understanding of neurological disorders. He also serves on the Research Consortium of Cure Alzheimer's Fund.

Awards

• 1993 W. Alden Spencer Award from Columbia University (shared with Richard Scheller)
• 1994 Wilhelm Feldberg Award
• 1997 Roger Eckert Award Lecture, Göttingen
• 1997 U.S. National Academy Award in Molecular Biology (shared with Richard Scheller)
• 2002 Elected to the National Academy of Sciences of the U.S.A.
• 2004 MetLife Award (shared with Roberto Malinow)
• Bristol-Myers Squibb Award for Distinguished Achievement in Neuroscience Research
• 2004 Ulf von Euler Award Lecture, Karolinska Institute
• 2007 Elected to the Institute of Medicine
• 2008 Bernhard Katz Award, Biophysical Society (shared with Reinhard Jahn)
• 2008 Passano Foundation Award
• 2010 Kavli Prize (shared with Richard Scheller and James Rothman)

 Key Papers

• Morris, S.J., Costello, M.J., Robertson, J.D., Südhof, T.C., Odenwald, W.F., and Haynes, D.H. (1983) Chromaffin granules as a model for membrane fusion: implications for exocytosis. J. Autonom. Nerv. Syst. 7, 19-33.
• Südhof, T.C., Goldstein, J.L., Brown, M.S., and Russell, D.W. (1985) The LDL receptor gene: A mosaic of exons shared with different proteins. Science 228, 815-822.
• Ma, P.T.S., Gil, G., Südhof, T.C., Bilheimer, D.W., Goldstein, J.L., and Brown, M.S. (1986) Mevinolin, an inhibitor of cholesterol synthesis, induces mRNA for low density lipoprotein receptor in livers of hamsters and rabbits. Proc. Natl. Acad. Sci. U.S.A. 83, 8370-8374.
• Dawson, P.A., Hofmann, S.L., Van Der Westhuyzen, D.R., Südhof, T.C., Brown, M.S., and Goldstein, J.L. (1988) Sterol-dependent repression of low density lipoprotein receptor promoter mediated by 16-base pair sequence adjacent to binding site for transcription factor SP1. J. Biol. Chem. 263, 3372-3379.
• Südhof, T.C. (1990) The structure of the human synapsin I gene and protein. J. Biol. Chem. 265, 7849-7852.
• Archer, B.T., III, Özcelik, T., Jahn, R., Francke, U., and Südhof, T.C. (1990) Structures and chromosomal localizations of two human genes encoding synaptobrevins 1 and 2. J. Biol. Chem. 265, 17267-17273.
• Perin, M.S., Johnston, P.A., Özcelik, T., Jahn, R., Francke, U., and Südhof, T.C. (1991) Structural and functional conservation of synaptotagmin (p65) in Drosophila and humans. J. Biol. Chem. 266, 615-622.
• Brose, N., Petrenko, A.G., Südhof, T.C., and Jahn, R. (1992) Synaptotagmin: A Ca2+ sensor on the synaptic vesicle surface. Science 256, 1021-1025.
• Ushkaryov, Y.A., Petrenko, A.G., Geppert, M., and Südhof, T.C. (1992) Neurexins: Synaptic cell surface proteins related to the α-latrotoxin receptor and laminin. Science 257, 50-56.
• Link, E., Edelmann, L., Chow, J.H., Binz, T., Yamasaki, S., Eisel, U., Baumert, M., Südhof, T.C., Niemann, H., and Jahn, R. (1992) Tetanus toxin action: Inhibition of neurotransmitter release linked to synaptobrevin proteolysis. Biochem. Biophys. Res. Comm. 189, 1017-1023.
• Blasi, J., Chapman, E.R., Link, E., Binz, T., Yamasaki, S., De Camilli, P., Südhof, T.C., Niemann, H., and Jahn, R. (1993) Botulinum neurotoxin A selectively cleaves the synaptic protein SNAP-25. Nature 365, 160-163.
• Rosahl, T.W., Geppert, M., Spillane, D., Herz, J., Hammer, R.E., Malenka, R.C., and Südhof, T.C. (1993) Short term synaptic plasticity is altered in mice lacking synapsin I. Cell 75, 661-670.
• Geppert, M., Bolshakov, V.Y., Siegelbaum, S.A., Takei, K., De Camilli, P., Hammer, R.E., and Südhof, T.C. (1994) The role of Rab3A in neurotransmitter release. Nature 369, 493-497.
• Geppert, M., Goda, Y., Hammer, R.E., Li, C., Rosahl, T.W., Stevens, C.F., and Südhof, T.C. (1994) Synaptotagmin I: A major Ca2+ sensor for transmitter release at a central synapse. Cell 79, 717-727.
• McMahon, H.T., and Südhof, T.C. (1995) Synaptic core complex of synaptobrevin, syntaxin, and SNAPS forms high affinity α-SNAP binding site. J. Biol. Chem. 270, 2213-2217.
• Ullrich, B., Ushkaryov, Y.A., and Südhof, T.C. (1995) Cartography of neurexins: More than 1000 isoforms generated by alternative splicing and expressed in distinct subsets of neurons. Neuron 14, 497-507.
• Ichtchenko, K., Hata, Y., Nguyen, T., Ullrich, B., Missler, M., Moomaw, C., and Südhof, T.C. (1995) Neuroligin 1: A splice-site specific ligand for ß-neurexins. Cell 81, 435-443.
• Shao, X., Li, C., Fernandez, I., Zhang, X., Südhof, T.C., and Rizo, J. (1997) Synaptotagmin-syntaxin interaction: the C2-domain as a Ca2+-dependent electrostatic switch. Neuron 18, 133-142.
• Nguyen, T., and Südhof, T.C. (1997) Binding properties of neuroligin 1 and neurexin 1ß reveal function as heterophilic cell adhesion molecules. J. Biol. Chem. 272, 26032-26039.
• Okamoto, M., and Südhof, T.C. (1997) Mints: Munc18-interacting proteins in synaptic vesicle exocytosis. J. Biol. Chem. 272, 31459-31464.
• Betz, A., Ashery, U., Rickmann, M., Augustin, I., Neher, E., Südhof, T.C., Rettig, J., and Brose, N. (1998) Munc13-1 is a presynaptic phorbol ester-receptor that stimulates neurotransmitter release. Neuron 21, 123-126.
• Wang, Y., Sugita, S., and Südhof, T.C. (2000) The RIM/NIM family of neuronal SH3-domain proteins: interactions with Rab3 and a new class of neuronal SH3-domain proteins. J. Biol. Chem. 275, 20033-20044.
• Lonart, G., and Südhof, T.C. (2000) Assembly of SNARE core complexes occurs prior to neurotransmitter release to set the readily-releasable pool of synaptic vesicles. J. Biol. Chem. 275, 27703-27707.
• Schoch, S., Castillo, P.E., Jo, T., Mukherjee, K., Geppert, M., Wang, Y., Schmitz, F., Malenka, R.C., and Südhof, T.C. (2002) RIM1α forms a protein scaffold for regulating neurotransmitter release at the active zone. Nature 415, 321-326.
• Chen, X, Tomchick, D.R., Kovrigin, E., Arac, D., Machius, M., Südhof, T.C., and Rizo, J. (2002) Three-dimensional structure of the complexin/SNARE complex. Neuron 33, 397-409.
• Schlüter, O.M., Fornai, F., Alessandri, M.G., Takamori, S., Geppert, M., Jahn, R., and Südhof, T.C. (2003) Role of α-Synuclein in MPTP-Induced Parkinsonism in Mice. Neuroscience 118, 985-1002.
• Matos, M.F., Chen, X., Rizo, J., and Südhof, T.C. (2003) Evidence for SNARE zippering during Ca2+-triggered exocytosis in PC12 cells. Neuropharmacology 45, 777-786.
• Powell, C.M., Schoch, S., Monteggia, L., Barrot, M., Matos, M.F., Südhof, T.C., and Nestler, E.J. (2004) The Presynaptic Active Zone Protein RIM1α is Critical for Normal Associative Learning. Neuron 42, 143-153.
• Dulubova, I., Ho, A., Südhof, T.C., and Rizo, J. (2004) Three-Dimensional Structure of an Independently Folded Extracellular Domain of Human Amyloid-β Precursor Protein. Biochemistry 43, 9583-9588.
• Chubykin, A.A., Liu, X., Comoletti, D., Tsigelny, I., Taylor, P., and Südhof, T.C. (2005) Dissection of Synapse Induction by Neuroligins: Effect of a Neuroligin Mutation Associated with Autism. J. Biol. Chem. 280, 22365-22374.
• Borisovska, M., Zhao, Y., Tsytsyura, Y., Glyvuk, N., Takamori, S., Matti, U., Rettig, J., Südhof, T.C., and Bruns, D. (2005) v-SNAREs control exocytosis of vesicles from priming to fusion. EMBO J. 24, 2114-2126.
• Pang, Z.P., Shin, O-H., Meyer, A.C., Rosenmund, C., and Südhof, T.C. (2006) A gain-of-function mutation in synaptotagmin-1 reveals a critical role of Ca2+-dependent SNARE-complex binding in synaptic exocytosis. J. Neurosci. 26, 12556-12565.
• Tabuchi, K., Blundell, J., Etherton, M.R., Hammer, R.E., Liu, X., Powell, C.M., and Südhof, T.C. (2007) A Neuroligin-3 Mutation Implicated in Autism Increases Inhibitory Synaptic Transmission in Mice. Science 318, 71-76.
• Ho, A., Liu, X., and Südhof, T.C. (2008) Deletion of Mint proteins decreases amyloid production in transgenic mouse models of Alzheimer’s disease. J. Neurosci. 28, 14392-14400.
• Blundell, J., Tabuchi, K., Bolliger, M.F., Blaiss, C.A., Brose, N., Liu, X., Südhof, T.C., and Powell, C.M. (2008) Increased Anxiety-like Behavior in Mice Lacking the Inhibitory Synapse Cell Adhesion Molecule Neuroligin 2. Genes Brain Behav., in press.
• Ko, J., Fuccillo, M. V., Malenka, R. C., and Südhof, T.C. (2009) LRRTM2 Functions as a Neurexin Ligand in Promoting Excitatory Synapse Formation. Neuron 64: 791-798.