Citation
Zitman, F. M. P. (2010, January 20). Gangliosides and anti-ganglioside antibodies in neuromuscular synaptic function. Retrieved from https://hdl.handle.net/1887/14568
Version: Corrected Publisher’s Version
License: Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden
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Gangliosides and anti-ganglioside antibodies in
neuromuscular synaptic function
Gangliosides and anti-ganglioside antibodies in neuromuscular synaptic function
Proefschrift ter verkrijging van
de graad van Doctor aan de Universiteit Leiden,
op gezag van de Rector Magnificus prof. mr. P.F. van der Heijden, volgens besluit van het College voor Promoties
te verdedigen op woensdag 20 januari 2010 klokke 15.00 uur
door
Femke Maaike Petronella Zitman
geboren te Leiden in 1979
Prof. Dr. P.A. Van Doorn (Erasmus Universiteit Rotterdam)
The studies described in this thesis were supported by the Prinses
Beatrix Fonds (#MAR04-0213).
Putting on the spectacles of science in expectation of finding an answer to everything looked at signifies inner blindness.
-- Frank J. Dobie
Contents
Chapter 1 General introduction
Preface 10
Gangliosides 11
Neuromuscular junction 15
Ganglioside-mediated NMJ pathophysiology 20 Guillain-Barré syndrome and Miller Fisher syndrome 22
Mouse models 28
Aims and outlines of this thesis 30
Chapter 2 Gangliosides and neuromuscular synaptic function
Chapter 2.1 Neuromuscular synaptic function in mice lacking major subsets
of gangliosides 35
Chapter 2.2 Neuromuscular synaptic transmission in aged ganglioside-deficient
mice 53
Chapter 2.3 Total ganglioside ablation at mouse motor nerve terminals alters
neurotransmitter release level 67
Chapter 3 Pathophysiological roles of anti-ganglioside antibodies at the neuromuscular synapse
Chapter 3.1 The role of complement and complement regulators in mediating motor nerve terminal injury in murine models of Guillain-Barré
syndrome 75
Chapter 3.2 Eculizumab prevents anti-ganglioside antibody-mediated
neuropathy in a murine model 89 Chapter 3.3 C5 inhibitor rEV576 protects against neural injury in an in vitro
mouse model of Miller Fisher syndrome 105 Chapter 3.4 Neuropathophysiological potential of anti-ganglioside complex
sera at mouse neuromuscular junctions 115 Chapter 3.5 The neuropathic potential of anti-GM1 autoantibodies is regulated
by the local glycolipid environment in mice 125
Chapter 4 Summary and general conclusion
The role of gangliosides in NMJ neurotransmitter release 152 Interpretation and extrapolation of mouse studies 156
Clinical considerations 161
Conclusion 163
