Dept. of Microbiology and Immunobiology
Harvard Medical School
Department of Urology
Boston Children's Hospital
300 Longwood Ave
Boston, MA, 02115
Click here to visit the Dong Lab Website.
Our lab studies a fascinating family of bacterial toxins, botulinum neurotoxins (BoNTs). We also are interested in basic questions of cell biology of neurons, in particular synaptic vesicle exocytosis/trafficking and cytoskeleton remodeling in neurons.
BoNTs are a diverse family of bacterial toxins that cause the disease botulism in humans and animals. These toxins are utilized to treat a growing list of medical conditions ranging from muscle spasms to chronic pain. Humans and animals are usually exposed to BoNTs as a form of food poisoning due to ingesting BoNTs produced by bacteria in food sources. BoNTs are produced in a protein complex with accessory proteins, which protect toxins from degradation in the gastrointestinal environment and may also facilitate the absorption of toxins across the intestine epithelial cell barrier. The toxins then target and enter peripheral nerve terminals via receptor-mediated endocytosis. Once inside the neurons, BoNTs translocate across endosomal membrane and act as proteases cleaving three essential proteins (SNARE proteins) that mediate synaptic vesicle exocytosis. Along this long journey in vivo, BoNTs encounter and interact with two types of highly polarized cells: epithelial cells and neurons. Many questions are currently being investigated in our field to understand how BoNTs cross gut epithelial cells, how these toxins target neurons, how they translocate across endosomal membrane into cytosol, how they maintain their extremely long half-life inside neurons, and how they traffic inside neurons.
The goals of our research are to understand the molecular and cellular basis for BoNT actions, to improve and expand the therapeutic application of these toxins, and to broaden our understanding of the fundamental cellular processes targeted by these bacterial toxins. The current projects in the lab include the following topics:
1. Mechanisms and Applications of Neuronal Targeting for Botulinum Neurotoxins
2. BoNT-induced Neurodegeneration
3. Regulation of Cytoskeleton Remodeling by ROCO kinases
To address these questions, we utilize a variety of cell lines and primary cultured rodent neurons as cell models, and we employ a range of biochemical and cell biological approaches including protein engineering, crystal structural studies, imaging, electrophysiology, and genetically modified mouse models.
Peng L, Adler M, Demogines A, Borrell A, Liu H, Tao L, Tepp WH, Zhang SC, Johnson EA, Sawyer SL and Dong M (2014). "Widespread sequence variations in VAMP1 across vertebrates suggest a potential selective pressure from botulinum neurotoxins", PLoS Pathogen, (in press).
Lee K, Zhong X, Gu S, Kruel AM, Dornet MB, Perry K, Rummel A, Dong M, Jin R (2014). "Molecular basis for disruption of E-cadherin adhesion by botulinum neurotoxin A complex", Science, (in press).
Berntsson RP-A, Peng L, Svensson LM, Dong M*, Stenmark P* (2013). “Crystal structures of botulinum neurotoxin DC in complex with its protein receptors synaptotagmin I and II”, Structure, 21:1602. (*: co-corresponding authors)
Berntsson RP-A, Peng L, Dong M, Stenmark P (2013). “Structure of dual receptor binding to botulinum neurotoxin B”, Nature
Peng L, Berntsson RP-A, Tepp WH, Pitkin RM, Johnson EA, Stenmark P*, and Dong M* (2012). “Botulinum neurotoxin D-C uses synaptotagmin I/II as receptors and human synaptotagmin II is not an effective receptor for type B, D-C, and G toxins”, J. Cell Science, 125:3233. (*: co-corresponding authors)
Peng L, Tepp WH., Johnson EA., Dong M (2011). “Botulinum neurotoxin D uses synaptic vesicle protein SV2 and gangliosides as receptors”, PLoS Pathogen, 7:e1002008. PMCID: PMC3068998.
Dong M, Liu H, Tepp WH, Johnson EA, Janz R, Chapman ER (2008).“Glycosylated SV2A and SV2B mediate the entry of botulinum neurotoxin E into neurons”, Mol. Bio. Cell, 19(12):5226.
Chai Q*, Arndt JW*, Dong M*, Tepp WH, Johnson EA, Chapman ER, Stevens RC (2006). “Structural basis of cell surface receptor recognition by botulinum neurotoxin B”, Nature, 444 (7122) :1096. (*: equal contribution)
Dong M, Yeh F, Tepp WH, Dean C, Johnson EA, Janz R, Chapman ER (2006). “SV2 is the protein receptor for botulinum neurotoxin A”, Science, 312(5773):592.
Dong M, Tepp WH, Johnson EA, Chapman ER (2004). “Using fluorescent sensors to detect botulinum neurotoxin activity in vitro and in living cells”, PNAS (USA), 101(41): 14701.
Dong M, Richards DA, Goodnough MC, Tepp WH, Johnson EA, Chapman ER (2003). “Synaptotagmins I and II mediate entry of botulinum neurotoxin B into cells”, J.Cell Biol., 162(7):1293.