The overall goal of this proposal is to understand how clostridial neurotoxins interact with their target cells and to use this knowledge to develop effective inhibitors of the toxin-cell interaction. Three botulinum toxins (A,B and E) will be studied to determine whether observations made with one toxin (botulinum toxin A) might have general applicability. If the botulinum toxins behave similarly, comparisons will be made to tetanus toxin to determine what similarities exist between the two classes of neurotoxins. Specifically, studies of the binding of botulinum toxins B and E to G1b gangliosides and derivatives thereof will be carried out. Results will be compared to those obtained for botulinum toxin A and tetanus toxin. Accumulating evidence suggests that gangliosides may not be the only cell surface receptor for these neurotoxins. In recent studies, we have found that botulinum toxin A, its heavy chain and the carboxy terminal half of the heavy chain bind to synaptosomal proteins. Tetanus toxin also adhered to synaptosomal proteins but it had to be preincubated with GT1b in order to bind to protein. The protein adhered to by both neurotoxins has an apparent molecular weight of approximately 77 kDa and is glycosylated. Experiments designed to purify and characterize the approximately kDa protein will be continued, and the site(s) adhered to by the toxin will be identified as will the portion of the neurotoxin responsible for the binding, and in in vitro experiments designed to identify the functional aspects of specific interactions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI023721-04A2
Application #
3136048
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Project Start
1986-07-01
Project End
1994-06-30
Budget Start
1991-07-01
Budget End
1992-06-30
Support Year
4
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Thompson, J P; Schengrund, C L (1997) Oligosaccharide-derivatized dendrimers: defined multivalent inhibitors of the adherence of the cholera toxin B subunit and the heat labile enterotoxin of E. coli to GM1. Glycoconj J 14:837-45
Schengrund, C L; DasGupta, B R; Hughes, C A et al. (1996) Ganglioside-induced adherence of botulinum and tetanus neurotoxins to adducin. J Neurochem 66:2556-61
Schengrund, C L; DasGupta, B R; Ringler, N J (1993) Ganglioside GD3 enhances adherence of botulinum and tetanus neurotoxins to bovine brain synapsin I. Neurosci Lett 158:159-62
Schengrund, C L; Ringler, N J; Dasgupta, B R (1992) Adherence of botulinum and tetanus neurotoxins to synaptosomal proteins. Brain Res Bull 29:917-24
Schengrund, C L; DasGupta, B R; Ringler, N J (1991) Binding of botulinum and tetanus neurotoxins to ganglioside GT1b and derivatives thereof. J Neurochem 57:1024-32
Fueshko, S M; Schengrund, C L (1990) Murine neuroblastoma cells express ganglioside binding sites on their cell surface. J Neurochem 54:1791-7
Schengrund, C L (1990) The role(s) of gangliosides in neural differentiation and repair: a perspective. Brain Res Bull 24:131-41
Schengrund, C L; Ringler, N J (1989) Binding of Vibrio cholera toxin and the heat-labile enterotoxin of Escherichia coli to GM1, derivatives of GM1, and nonlipid oligosaccharide polyvalent ligands. J Biol Chem 264:13233-7
Schengrund, C L; Prouty, C (1988) Oligosaccharide portion of GM1 enhances process formation by S20Y neuroblastoma cells. J Neurochem 51:277-82
Schengrund, C L; Shochat, S J (1988) Gangliosides in neuroblastomas. Neurochem Pathol 8:189-202