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Alpha-synuclein deficiency in the C57BL/6JOlaHsd strain does not modify disease progression in the ME7-model of prion
A A Asuni1, K Hilton, Z Siskova
1CNS Inflammation Group, University of Southampton, UK. asuni@mac.com
Abstract:
We previously detailed how intrahippocampal inoculation of C57BL/6J mice with murine modified scrapie (ME7) leads to chronic neurodegeneration (Cunningham C, Deacon R, Wells H, Boche D, Waters S, Diniz CP, Scott H, Rawlins JN, Perry VH (2003) Eur J Neurosci 17:2147-2155.). Our characterization of the ME7-model is based on inoculation of this murine modified scrapie agent into C57BL/6J mice from Harlan laboratories. This agent in the C57BL/6J host generates a disease that spans a 24-week time course. The hippocampal pathology shows progressive misfolded prion (PrP(Sc)) deposition, astrogliosis and leads to behavioural dysfunction underpinned by the early synaptic loss that precedes neuronal death. The Harlan C57BL/6J, although widely used as a wild type mouse, are a sub-strain harbouring a spontaneous deletion of alpha-synuclein with the full description C57BL/6JOlaHsd. Recently alpha-synuclein has been shown to ameliorate the synaptic loss in a mouse model lacking the synaptic chaperone CSP-alpha. This opens a potential confound of the ME7-model, particularly with respect to the signature synaptic loss that underpin the physiological and behavioural dysfunction. To investigate if this strain-selective loss of a candidate disease modifier impacts on signature ME7 pathology, we compared cohorts of C57BL/6JOlaHsd (alpha-synuclein negative) with the founder strain from Charles Rivers (C57BL/6JCrl, alpha-synuclein positive). There were subtle changes in behaviour when comparing control animals from the two sub-strains indicating potentially significant consequences for studies assuming neurobiogical identity of both strains. However, there was no evidence that the absence of alpha-synuclein modifies disease. Indeed, accumulation of PrP(Sc), synaptic loss and the behavioural dysfunction associated with the ME7-agent was the same in both genetic backgrounds. Our data suggest that alpha-synuclein deficiency does not contribute to the compartment specific processes that give rise to prion disease mediated synaptotoxicity and neurodegeneration.
Insights
Alpha-synuclein deficiency does not alter prion disease progression or synaptic loss in the ME7 mouse model. This finding clarifies potential confounds in prion disease research using C57BL/6J mice.
Area of Science:
- Neuroscience
- Prion Disease Research
- Mouse Models of Neurodegeneration
Background:
- The ME7 prion disease model in C57BL/6J mice exhibits chronic neurodegeneration, characterized by prion deposition, astrogliosis, synaptic loss, and behavioral dysfunction.
- A specific sub-strain of C57BL/6J mice (C57BL/6JOlaHsd) lacks alpha-synuclein, a protein recently shown to protect against synaptic loss in other models.
- This alpha-synuclein deficiency in the ME7 model could confound interpretations of synaptic loss and associated dysfunction.
Purpose of the Study:
- To investigate whether the absence of alpha-synuclein influences the characteristic pathology and behavioral deficits in the ME7 prion disease model.
- To compare disease progression and synaptic integrity between C57BL/6J mice with and without alpha-synuclein.
Main Methods:
- Comparison of two C57BL/6J sub-strains: C57BL/6JOlaHsd (alpha-synuclein negative) and C57BL/6JCrl (alpha-synuclein positive).
- Intrahippocampal inoculation with the ME7 murine modified scrapie agent.
- Assessment of behavioral changes, prion (PrP(Sc)) deposition, astrogliosis, and synaptic loss over a 24-week disease course.
Main Results:
- Subtle behavioral differences were observed between control animals of the two sub-strains, suggesting potential issues with assuming neurobiological identity.
- Despite the absence of alpha-synuclein in one cohort, there was no evidence of modified disease progression.
- Accumulation of PrP(Sc), synaptic loss, and behavioral dysfunction were consistent across both alpha-synuclein positive and negative C57BL/6J backgrounds.
Conclusions:
- Alpha-synuclein deficiency does not significantly impact the development or severity of ME7 prion disease-mediated neurodegeneration.
- The synaptic loss and neurotoxic processes in this prion disease model are independent of alpha-synuclein presence.
- Findings suggest that the ME7 model can be reliably used across C57BL/6J sub-strains regarding alpha-synuclein status for studying prion pathogenesis.
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