RNA Interference of Human α-Synuclein in Mouse.
RNA Interference of Human α-Synuclein in Mouse.
复制标题
人α-突触核蛋白在小鼠中的RNA干扰。
DOI：
10.3389/fneur.2017.00013
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发表时间：
2017
影响因子：
3.4
通讯作者：
Narayanan NS
中科院分区：
文献类型：
--
作者：
Kim YC;Miller A;Lins LC;Han SW;Keiser MS;Boudreau RL;Davidson BL;Narayanan NS
α-Synuclein is postulated to play a key role in the pathogenesis of Parkinson’s disease (PD). Aggregates of α-synuclein contribute to neurodegeneration and cell death in humans and in mouse models of PD. Here, we use virally mediated RNA interference to knockdown human α-synuclein in mice. We used an siRNA design algorithm to identify eight siRNA sequences with minimal off-targeting potential. One RNA-interference sequence (miSyn4) showed maximal protein knockdown potential in vitro. We then designed AAV vectors expressing miSyn4 and injected them into the mouse substantia nigra. miSyn4 was robustly expressed and did not detectably change dopamine neurons, glial proliferation, or mouse behavior. We then injected AAV2-miSyn4 into Thy1-hSNCA mice over expressing α-synuclein and found decreased human α-synuclein (hSNCA) in both midbrain and cortex. In separate mice, co-injection of AAV2-hSNCA and AAV2-miSyn4 demonstrated decreased hSNCA expression and rescue of hSNCA-mediated behavioral deficits. These data suggest that virally mediated RNA interference can knockdown hSNCA in vivo, which could be helpful for future therapies targeting human α-synuclein.
