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bioRxiv · 10.1101/2023.10.27.564027

G51D mutation of the endogenous rat Snca gene disrupts synaptic localisation of α-synuclein priming for Lewy-like pathology

West, S.·Natalwala, A.·Dolt, K. S.·Lamont, D. J.·McMillan, M.·Luk, K.·Mashimo, T.·Kunath, T.
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Abstract

Point mutations in the SNCA gene, encoding -synuclein (Syn), are a known cause of familial Parkinsons disease. The G51D mutation causes early onset neurodegeneration with complex pathology. We used CRISPR/Cas9 in rats to introduce the G51D mutation into the endogenous Snca gene. Co-localisation immunostaining studies with synaptic proteins showed that SynG51D protein is no longer efficiently localised to synapses. Furthermore, biochemical isolation of synaptosomes from rat cortex demonstrated a significant depletion of Syn in SncaG51D/+ and SncaG51D/G51D rats. Unbiased proteomic investigation of the cortex identified significant synaptic dysregulation in SncaG51D/G51D animals. Finally, we compared the propensity for Lewy-like pathology of Snca+/+ and SncaG51D/G51D rats by stereotaxically delivering Syn pre-formed fibrils (PFFs) into the pre-frontal cortex. At an early time-point, 6 weeks post-injection, we observed discrete Lewy-like structures positive for phosphoserine-129-Syn (pS129-Syn) only in SncaG51D/G51D brains. At 26 weeks post-injection of PFFs SncaG51D/G51D brains exhibited intense, discrete pS129-Syn-positive structures, while Snca+/+ brains exhibited diffuse pS129-Syn immunostaining. Quantification of discrete pS129-Syn-positive structures revealed the striatum of SncaG51D/G51D rats had significantly more Lewy-like pathology than Snca+/+ rats. In summary, this novel SncaG51D rat model exhibits molecular characteristics of early synaptic dysfunction and is primed for Syn pathology.

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West, S., Natalwala, A., Dolt, K. S., Lamont, D. J., McMillan, M., Luk, K., Mashimo, T., Kunath, T.. 2023-10-30. G51D mutation of the endogenous rat Snca gene disrupts synaptic localisation of α-synuclein priming for Lewy-like pathology. https://doi.org/10.1101/2023.10.27.564027

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