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

Matthew J Davies,Matthew Cooper,V Hugh Perry,Vincent O’Connor

doi:10.1016/j.neulet.2015.01.053

Matthew J Davies, Matthew Cooper + Show 2 more

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https://doi.org/10.1016/j.neulet.2015.01.053

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Journal: Neuroscience letters	Publication Date: Jan 23, 2015
Citations: 18	License type: cc-by

Affiliation: University of Southampton

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 (CSPα), which regulates refolding pathways at the synapse, exhibits an early decline during chronic neurodegeneration implicating it as a mediator of disease mechanisms. CSPα null mice develop a progressive neuronal dysfunction through disruption of the integrity of presynaptic function. In this study, we investigated whether reduced expression of CSPα would exacerbate ME7 prion disease. Wild type (+/+) and heterozygous (+/−) mice, which express about a ∼50% reduction in CSPα, 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 CSPα on disease. Behavioural tests revealed no change in the progression of disease in ME7–CSPα +/− animals compared to ME7–CSPα +/+ animals. In addition, the accumulation of misfolded PrPSc, 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 CSPα.

Highlights

Prion diseases, are a group of rare and fatal neurodegenerative diseases of human and animals [1] involving the conversion of the cellular prion protein (PrPc) into a misfolded form (PrPSc), which accumulates and deposits as amyloid plaques [2]
At 18 w.p.i., motor deficits become apparent, as evidenced by declining performance in the inverted screen test [10,21]. This decline in behavioural performance as a consequence of prion disease is apparent in the behavioural tests performed as part of this study, with both ME7–CSP␣ +/+ and +/− animals showing progressively decreasing burrowing behaviour (Fig. 1A and B) and glucose consumption (Fig. 1C), increased distance travelled (Fig. 1D) and rears (Fig. 1E) and reduced strength (Fig. 1F) compared to NBH-animals
CSP␣ +/− animals have a higher baseline level in the number of pellets burrowed in 2 h (Fig. 1A) and overnight (Fig. 1B), the amount of glucose consumed (Fig. 1C), distance travelled (Fig. 1D) and rears (Fig. 1E), there was no difference in the progression of the behavioural decline in ME7-animals between CSP␣ genotypes (Fig. 1A–F)

Summary

Introduction

Prion diseases, are a group of rare and fatal neurodegenerative diseases of human and animals [1] involving the conversion of the cellular prion protein (PrPc) into a misfolded form (PrPSc), which accumulates and deposits as amyloid plaques [2]. Pathology in prion-infected mice develops in a well-defined and predictable manner, over a time course dependent on the prion strain used This well-defined temporal progression renders prion-based models ideal for investigating significant disease events and underlying mechanisms of pathology [5,6,10,11]

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