GENERATING A NOVEL DOUBLE TRANSGENIC MOUSE MODEL FOR SELECTIVE ABLATION OF ALPHA-SYNUCLEIN IN THE BRAIN

Aggregated alpha-synuclein (a-syn) is the histopathological hallmark protein linked to Parkinson’s Disease and SNCA is the gene encoding this protein. It is still a question whether a-syn originating from the periphery contributes to pathology in the brain. This study aimed to develop a novel double-transgenic mouse model where a-syn in the CNS is selectively ablated. To this end, a “Nestin-cre : Snca flox” mouse was generated to specifically delete SNCA in neural cells to stop a-syn production in the brain. Two transgenic mouse strains were used: “Nestin-Cre” (B6.Cg-Tg(Nes-cre)1Kln/J) and “SNCAflox delta neo” (B6(Cg)-Snca^tm1.1Vlb/J). Initial crossing of these strains produced a heterozygous double-transgenic offspring. In a second step, heterozygous double-transgenic offspring were intercrossed to produce mice with the desired genotypes for analysis. Finally, SNCA deletion was verified through a-syn targeted ELISA and immunohistochemical analyses on brains from experimental groups. Brain a-syn levels normalized to total brain protein were significantly lower in homozygous double-transgenic mice (mean = 67.9) compared with wild-type mice (mean = 1088.9), representing a 93.8% decrease (p<0.01), as shown in Graph 1. Also, immunohistochemistry further confirmed markedly reduced α-syn expression in brain sections of homozygous double-transgenic mice compared to wild-type mice. Generation of a novel double-transgenic mouse model that enables the successful deletion of the Snca gene specifically in neural cells was accomplished. This model offers the capacity to study a-syn related processes such as production, transport, and aggregation of peripherally produced a-syn in the CNS.