The mechanism of localization and attachment of collagen tailed acetylcholinesterase at the mammalian neuromuscular junction
Date of Award
Doctor of Philosophy (Ph.D.)
First Committee Member
Richard Rotundo, Committee Chair
The enzyme acetylcholinesterase (AChE) is responsible for terminating neuromuscular transmission at the neuromuscular junction (NMJ) by hydrolyzing the neurotransmitter acetylcholine (ACh). The predominant form of AChE present at the neuromuscular synapses of mammalian skeletal muscle is the collagen-tailed asymmetric or A12 form. Our current model of extracellular matrix specialization at the NMJ suggests that the collagenic-tailed form of acetylcholinesterase is localized in association with the transmembrane dystroglycan complex via binding of its collagen-like tail (ColQ to the proteoglycan perlecan. Presently, the specific amino acids in ACNE that are necessary for binding to post synaptic basal lamina and the molecular mechanism by which the synaptic form of acetylcholinesterase is attached to the neuromuscular junction are unknown. The importance of synapse-resident AChE is evidenced by the crippling phenotype exhibited by patients with congenital defects in this enzyme and the rapidity of death following exposure of individuals to nerve gases. Humans with a congenital myasthenic (CMS) syndrome with endplate AChE deficiency synthesize the A12 AChE form yet do not have the enzyme localized at the synapse. Several specific single amino acid mutations, as well as deletions and truncations, in the C-terminal domain (CTD) of the collagenic tail (ColQ) subunit have been identified in these patients with endplate AChE deficiency. Experimental results suggest that the basal lamina resident heparin sulfate proteoglycan (HSPG) perlecan is a binding partner for AChE at the mammalian NMJ and that the C-terminal domain of ColQ plays an essential role in anchoring the AChE asymmetric form into the synaptic basal lamina. Given the diverse nature of this molecule and the global significance of its function in mammalian systems, it is important to understand the interactions of AChE at neuromuscular synapses. The overall goal of this dissertation is to determine the mechanism of localization and attachment of AChE to mammalian NMJs and utilize this knowledge to examine realistic therapies for neuromuscular pathologies associated with AChE function and localization.
Biology, Molecular; Biology, Neuroscience; Biology, Cell
Kimbell, Lewis Mercer Iii., "The mechanism of localization and attachment of collagen tailed acetylcholinesterase at the mammalian neuromuscular junction" (2006). Dissertations from ProQuest. 2454.