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Reduced expression of the presynaptic co-chaperone cysteine string protein alpha (CSP?) does not exacerbate experimentally-induced ME7 prion disease

Reduced expression of the presynaptic co-chaperone cysteine string protein alpha (CSP?) does not exacerbate experimentally-induced ME7 prion disease
Reduced expression of the presynaptic co-chaperone cysteine string protein alpha (CSP?) does not exacerbate experimentally-induced ME7 prion disease
Infection of mice with the ME7 prion agent results in well-characterised neuropathological changes, which includes vacuolation, neurodegeneration and synaptic degeneration. Presynaptic dysfunction and degeneration is apparent through the progressive reduction in synaptic vesicle proteins and eventual loss of synapses. Cysteine string protein alpha (CSP?), which regulates refolding pathways at the synapse, exhibits an early decline during chronic neurodegeneration implicating it as a mediator of disease mechanisms. CSP? null mice develop a progressive neuronal dysfunction through disruption of the integrity of presynaptic function. In this study, we investigated whether reduced expression of CSP? would exacerbate ME7 prion disease. Wild type (+/+) and heterozygous (+/-) mice, which express about a ?50% reduction in CSP?, were used as a distinct genetic background on which to impose prion disease. +/+ and +/ - mice were inoculated with brain homogenate from either a normal mouse brain (NBH) or from the brain of a mouse which displayed clinical signs of prion disease (ME7). Behavioural tests, western blotting and immunohistochemistry, which resolve key elements of synaptic dysfunction, were used to assess the effect of reduced CSP? on disease. Behavioural tests revealed no change in the progression of disease in ME7-CSP? +/- animals compared to ME7-CSP? +/+ animals. In addition, the accumulation of misfolded PrP(Sc), the diseased associated gliosis or synaptic loss were not different. Thus, the misfolding events that generate synaptic dysfunction and lead to synaptic loss are unlikely to be mediated by a disease associated decrease in the refolding pathways associated with CSP?.
CSP?, gliosis, ME7, PrPSc, synaptic loss
0304-3940
138-43
Davies, Matthew J.
7ae0a18b-8f88-48af-b6a0-788988b4f681
Cooper, Matthew
e8f307fe-15c1-489f-82b4-439a60b4f089
Perry, V. Hugh
8f29d36a-8e1f-4082-8700-09483bbaeae4
O'Connor, Vincent
8021b06c-01a0-4925-9dde-a61c8fe278ca
Davies, Matthew J.
7ae0a18b-8f88-48af-b6a0-788988b4f681
Cooper, Matthew
e8f307fe-15c1-489f-82b4-439a60b4f089
Perry, V. Hugh
8f29d36a-8e1f-4082-8700-09483bbaeae4
O'Connor, Vincent
8021b06c-01a0-4925-9dde-a61c8fe278ca

Davies, Matthew J., Cooper, Matthew, Perry, V. Hugh and O'Connor, Vincent (2015) Reduced expression of the presynaptic co-chaperone cysteine string protein alpha (CSP?) does not exacerbate experimentally-induced ME7 prion disease. Neuroscience Letters, 589, 138-43. (doi:10.1016/j.neulet.2015.01.053). (PMID:9009832)

Record type: Article

Abstract

Infection of mice with the ME7 prion agent results in well-characterised neuropathological changes, which includes vacuolation, neurodegeneration and synaptic degeneration. Presynaptic dysfunction and degeneration is apparent through the progressive reduction in synaptic vesicle proteins and eventual loss of synapses. Cysteine string protein alpha (CSP?), which regulates refolding pathways at the synapse, exhibits an early decline during chronic neurodegeneration implicating it as a mediator of disease mechanisms. CSP? null mice develop a progressive neuronal dysfunction through disruption of the integrity of presynaptic function. In this study, we investigated whether reduced expression of CSP? would exacerbate ME7 prion disease. Wild type (+/+) and heterozygous (+/-) mice, which express about a ?50% reduction in CSP?, were used as a distinct genetic background on which to impose prion disease. +/+ and +/ - mice were inoculated with brain homogenate from either a normal mouse brain (NBH) or from the brain of a mouse which displayed clinical signs of prion disease (ME7). Behavioural tests, western blotting and immunohistochemistry, which resolve key elements of synaptic dysfunction, were used to assess the effect of reduced CSP? on disease. Behavioural tests revealed no change in the progression of disease in ME7-CSP? +/- animals compared to ME7-CSP? +/+ animals. In addition, the accumulation of misfolded PrP(Sc), the diseased associated gliosis or synaptic loss were not different. Thus, the misfolding events that generate synaptic dysfunction and lead to synaptic loss are unlikely to be mediated by a disease associated decrease in the refolding pathways associated with CSP?.

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Accepted/In Press date: 20 January 2015
e-pub ahead of print date: 23 January 2015
Published date: 4 March 2015
Keywords: CSP?, gliosis, ME7, PrPSc, synaptic loss
Organisations: Biomedicine

Identifiers

Local EPrints ID: 377499
URI: https://eprints.soton.ac.uk/id/eprint/377499
ISSN: 0304-3940
PURE UUID: 65bdf75d-79e2-40d1-aa9f-3155305df8af

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Date deposited: 15 Jun 2015 14:07
Last modified: 19 Jul 2019 20:43

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