In vivo silencing of alpha-synuclein using naked siRNA.
In vivo silencing of alpha-synuclein using naked siRNA.
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DOI：
10.1186/1750-1326-3-19
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发表时间：
2008-11-01
影响因子：
15.1
通讯作者：
Farrer, Matthew J.
中科院分区：
文献类型：
--
作者：
Lewis, Jada;Melrose, Heather;Bumcrot, David;Hope, Andrew;Zehr, Cynthia;Lincoln, Sarah;Braithwaite, Adam;He, Zhen;Ogholikhan, Sina;Hinkle, Kelly;Kent, Caroline;Toudjarska, Ivanka;Charisse, Klaus;Braich, Ravi;Pandey, Rajendra K.;Heckman, Michael;Maraganore, Demetrius M.;Crook, Julia;Farrer, Matthew J.
在具有倍增突变的家族中，α-突触核蛋白（SNCA）的过度表达导致帕金森综合征和随后的痴呆，其特征在于死后的弥漫性路易体病。SNCA的遗传变异有助于特发性帕金森病（PD）的风险，可能是过度表达的结果。因此，SNCA下调是PD的有效治疗靶点。我们已经鉴定了在体外减少SNCA的人和鼠特异性siRNA分子。作为概念的证明，我们证明了将化学修饰的（裸的）鼠特异性siRNA直接输注到海马中显著降低了SNCA水平。海马和皮质中SNCA的减少持续输注后至少1周，输注后3周恢复至接近对照水平。我们已经开发了裸基因特异性siRNA，其在体内沉默SNCA的表达。这种方法可能有助于我们理解SNCA的内源性功能平衡，其在疾病中的作用，并最终作为SNCA过表达引起的α-突触核蛋白病的治疗策略。
Overexpression of α-synuclein (SNCA) in families with multiplication mutations causes parkinsonism and subsequent dementia, characterized by diffuse Lewy Body disease post-mortem. Genetic variability in SNCA contributes to risk of idiopathic Parkinson's disease (PD), possibly as a result of overexpression. SNCA downregulation is therefore a valid therapeutic target for PD. We have identified human and murine-specific siRNA molecules which reduce SNCA in vitro. As a proof of concept, we demonstrate that direct infusion of chemically modified (naked), murine-specific siRNA into the hippocampus significantly reduces SNCA levels. Reduction of SNCA in the hippocampus and cortex persists for a minimum of 1 week post-infusion with recovery nearing control levels by 3 weeks post-infusion. We have developed naked gene-specific siRNAs that silence expression of SNCA in vivo. This approach may prove beneficial toward our understanding of the endogenous functional equilibrium of SNCA, its role in disease, and eventually as a therapeutic strategy for α-synucleinopathies resulting from SNCA overexpression.
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影响因子：
168.9
作者：
Chartier-Harlin, MC;Kachergus, J;Destée, A
通讯作者：
Destée, A
影响因子：
9.9
作者：
Ahn, T. -B.;Kim, S. Y.;Jeon, B. S.
通讯作者：
Jeon, B. S.
影响因子：
56.9
作者：
Singleton, AB;Farrer, M;Gwinn-Hardy, K
通讯作者：
Gwinn-Hardy, K
影响因子：
11
作者：
Thakker, DR;Natt, F;Cryan, JF
通讯作者：
Cryan, JF
DOI：
10.1073/pnas.0406214101
发表时间：
2004-12-07
影响因子：
11.1
作者：
Thakker, DR;Natt, F;Cryan, JF
通讯作者：
Cryan, JF