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Title: A VAP-33 homologue : a possible role in intracellular signalling and membrane structure in neurons
Author: Middleton, Susan
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2006
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VAMP/synaptobrevin-associated protein of 33kDa (VAP33) was first identified in Alplasia Californica. There are two mammalian homologues of VAP33 named VAPA and VAPB both of which are ubiquitously expressed and have been found to associate with the endoplasmic reticulum (ER). These proteins are type II membrane proteins and have a N-terminal Major Sperm Protein (MSP) domain, a coiled-coil domain and a transmembrane domain. Deletion of the yeast VAP-A homologue, SCS2, disrupts the regulation of the inositol biosynthesis system and the Unfolded Protein Response (UPR) from the ER. Also in C. elegans the MSP is involved in structural motility and has an Eph receptor-dependent signalling function during oocyte maturation. This raises the interesting possibility that in addition to a structural role, the VAP proteins may also provide a signalling function. We have found that when the VAPA MSP domain alone is expressed in neurons it aggregates, activates components of ER stress pathways, and induces apoptosis via caspase 3. It is possible, therefore, that VAP proteins may activate intracellular signalling pathways through regulated interactions of their MSP domains, and that aggregation of MSP-containing polypeptides may disrupt these systems. These results have clinical implications as a missense mutation in the VAPB gene has recently been identified as being associated with an atypical form of amyotrophic lateral sclerosis (ALS8) in a Brazilian family. Wild type VAPA and B are expressed in motor neurons but only accumulate at the synaptic junction in neonates. We introduced the P56S mutation into mouse VAPB and expressed it as a GFP-fusion protein neurons. The substitution has a profound effect on the subcellular distribution of the protein, causing accumulation of membrane associated protein aggregates.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available