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|Title:||Prion protein facilitates synaptic vesicle release by enhancing release probability|
|Authors:||Robinson, Susan W.|
Nugent, Marie L.
Steinert, Joern R.
|Publisher:||Oxford University Press (OUP)|
|Citation:||Human Molecular Genetics (2014) 23 (17): 4581-4596.|
|Abstract:||The cellular prion protein (PrPC) has been implicated in several neurodegenerative diseases as a result of protein misfolding. In humans, prion disease occurs typically with a sporadic origin where uncharacterized mechanisms induce spontaneous PrPC misfolding leading to neurotoxic PrP-scrapie formation (PrPSC). The consequences of misfolded PrPC signalling are well characterized but little is known about the physiological roles of PrPC and its involvement in disease. Here we investigated wild-type PrPC signalling in synaptic function as well as the effects of a disease-relevant mutation within PrPC (proline-to-leucine mutation at codon 101). Expression of wild-type PrPC at the Drosophila neuromuscular junction leads to enhanced synaptic responses as detected in larger miniature synaptic currents which are caused by enlarged presynaptic vesicles. The expression of the mutated PrPC leads to reduction of both parameters compared with wild-type PrPC. Wild-type PrPC enhances synaptic release probability and quantal content but reduces the size of the ready-releasable vesicle pool. Partially, these changes are not detectable following expression of the mutant PrPC. A behavioural test revealed that expression of either protein caused an increase in locomotor activities consistent with enhanced synaptic release and stronger muscle contractions. Both proteins were sensitive to proteinase digestion. These data uncover new functions of wild-type PrPC at the synapse with a disease-relevant mutation in PrPC leading to diminished functional phenotypes. Thus, our data present essential new information possibly related to prion pathogenesis in which a functional synaptic role of PrPC is compromised due to its advanced conversion into PrPSC thereby creating a lack-of-function scenario.|
|Rights:||© The Author 2014. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.|
|Appears in Collections:||Published Articles, MRC Toxicology Unit|
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