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The role of activity in synaptic degeneration in a protein misfolding disease, prion disease

The role of activity in synaptic degeneration in a protein misfolding disease, prion disease
The role of activity in synaptic degeneration in a protein misfolding disease, prion disease
In chronic neurodegenerative diseases associated with aggregates of misfolded proteins (such as Alzheimer's, Parkinson's and prion disease), there is an early degeneration of presynaptic terminals prior to the loss of the neuronal somata. Identifying the mechanisms that govern synapse degeneration is of paramount importance, as cognitive decline is strongly correlated with loss of presynaptic terminals in these disorders. However, very little is known about the processes that link the presence of a misfolded protein to the degeneration of synapses. It has been suggested that the process follows a simple linear sequence in which terminals that become dysfunctional are targeted for death, but there is also evidence that high levels of activity can speed up degeneration. To dissect the role of activity in synapse degeneration, we infused the synaptic blocker botulinum neurotoxin A (BoNT/A) into the hippocampus of mice with prion disease and assessed synapse loss at the electron microscopy level. We found that injection of BoNT/A in naïve mice caused a significant enlargement of excitatory presynaptic terminals in the hippocampus, indicating transmission impairment. Long-lasting blockade of activity by BoNT/A caused only minimal synaptic pathology and no significant activation of microglia. In mice with prion disease infused with BoNT/A, rates of synaptic degeneration were indistinguishable from those observed in control diseased mice. We conclude that silencing synaptic activity neither prevents nor enhances the degree of synapse degeneration in prion disease. These results challenge the idea that dysfunction of synaptic terminals dictates their elimination during prion-induced neurodegeneration.
1932-6203
e41182
Caleo, Matteo
f40884a6-2b30-4dc8-bbb8-47dfdc5cf2bc
Restani, Laura
6c20fd33-f21d-491b-bd4f-e37846571393
Vannini, Eleonora
34c64fdb-87cc-4cb8-abf0-a73ce34efe93
Siskova, Zuzana
637bfeb5-fb00-4b28-b4a8-394426ded077
Al-Malki, Hussain
f4f2db11-ed59-48dc-9ce5-b32eab9e1733
Morgan, Ruth
fb10246b-58ac-471a-adbf-048ac04e4d91
O'Connor, Vincent
8021b06c-01a0-4925-9dde-a61c8fe278ca
Perry, V Hugh
8f29d36a-8e1f-4082-8700-09483bbaeae4
Caleo, Matteo
f40884a6-2b30-4dc8-bbb8-47dfdc5cf2bc
Restani, Laura
6c20fd33-f21d-491b-bd4f-e37846571393
Vannini, Eleonora
34c64fdb-87cc-4cb8-abf0-a73ce34efe93
Siskova, Zuzana
637bfeb5-fb00-4b28-b4a8-394426ded077
Al-Malki, Hussain
f4f2db11-ed59-48dc-9ce5-b32eab9e1733
Morgan, Ruth
fb10246b-58ac-471a-adbf-048ac04e4d91
O'Connor, Vincent
8021b06c-01a0-4925-9dde-a61c8fe278ca
Perry, V Hugh
8f29d36a-8e1f-4082-8700-09483bbaeae4

Caleo, Matteo, Restani, Laura, Vannini, Eleonora, Siskova, Zuzana, Al-Malki, Hussain, Morgan, Ruth, O'Connor, Vincent and Perry, V Hugh (2012) The role of activity in synaptic degeneration in a protein misfolding disease, prion disease. PLoS ONE, 7 (7), e41182. (doi:10.1371/journal.pone.0041182). (PMID:22815961)

Record type: Article

Abstract

In chronic neurodegenerative diseases associated with aggregates of misfolded proteins (such as Alzheimer's, Parkinson's and prion disease), there is an early degeneration of presynaptic terminals prior to the loss of the neuronal somata. Identifying the mechanisms that govern synapse degeneration is of paramount importance, as cognitive decline is strongly correlated with loss of presynaptic terminals in these disorders. However, very little is known about the processes that link the presence of a misfolded protein to the degeneration of synapses. It has been suggested that the process follows a simple linear sequence in which terminals that become dysfunctional are targeted for death, but there is also evidence that high levels of activity can speed up degeneration. To dissect the role of activity in synapse degeneration, we infused the synaptic blocker botulinum neurotoxin A (BoNT/A) into the hippocampus of mice with prion disease and assessed synapse loss at the electron microscopy level. We found that injection of BoNT/A in naïve mice caused a significant enlargement of excitatory presynaptic terminals in the hippocampus, indicating transmission impairment. Long-lasting blockade of activity by BoNT/A caused only minimal synaptic pathology and no significant activation of microglia. In mice with prion disease infused with BoNT/A, rates of synaptic degeneration were indistinguishable from those observed in control diseased mice. We conclude that silencing synaptic activity neither prevents nor enhances the degree of synapse degeneration in prion disease. These results challenge the idea that dysfunction of synaptic terminals dictates their elimination during prion-induced neurodegeneration.

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Published date: 16 July 2012
Organisations: Faculty of Natural and Environmental Sciences, Biomedicine, Centre for Biological Sciences

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Local EPrints ID: 341937
URI: https://eprints.soton.ac.uk/id/eprint/341937
ISSN: 1932-6203
PURE UUID: 37a21780-a9dc-44be-8685-0976be4176bd

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Date deposited: 08 Aug 2012 13:59
Last modified: 18 Jul 2017 05:31

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