A Brain-Penetrant Stearoyl-CoA Desaturase Inhibitor Reverses α-Synuclein Toxicity.
A Brain-Penetrant Stearoyl-CoA Desaturase Inhibitor Reverses α-Synuclein Toxicity.
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DOI：
10.1007/s13311-022-01199-7
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发表时间：
2022-04
影响因子：
5.7
通讯作者：
Scannevin, Robert H.
中科院分区：
文献类型：
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作者：
Nuber, Silke;Chung, Chee Yeun;Tardiff, Daniel F.;Bechade, Pascal A.;McCaffery, Thomas D.;Shimanaka, Kazuma;Choi, Jeonghoon;Chang, Belle;Raja, Waseem;Neve, Esther;Burke, Christopher;Jiang, Xin;Xu, Ping;Khurana, Vikram;Dettmer, Ulf;Fanning, Saranna;Rhodes, Kenneth J.;Selkoe, Dennis J.;Scannevin, Robert H.
越来越多的证据表明，帕金森病（PD）损害中脑多巴胺能、皮质和其他神经元亚型，这在很大程度上是由于富含脂质和囊泡的α-突触核蛋白（αSyn）细胞毒性内含物的积聚。我们以前确定硬脂酰辅酶A去饱和酶（SCD）作为突触核蛋白病的潜在治疗靶点。开发了一种脑渗透性SCD抑制剂YTX-7739，并已进入1期临床试验。在这里，我们报告了YTX-7739在各种体外和体内PD模型中逆转病理性αSyn表型的疗效。在基于细胞的试验中，YTX-7739减少了α Syn介导的神经元死亡，逆转了扩增的E46 K（“3 K”）αSyn的异常膜相互作用，并防止了A53 T和αSyn三倍患者源性神经球中的病理表型，包括失调的脂肪酸谱和pS129 αSyn积累。在3 K PD样小鼠中，YTX-7739穿过血脑屏障，减少不饱和脂肪酸，并防止进行性运动缺陷。YTX-7739处理和通过缺失一个拷贝的SCD 1基因（SKO）降低SCD活性均恢复了3 K αSyn小鼠中的生理αSyn四聚体与单体比例、多巴胺能完整性和神经元存活。YTX-7739可有效降低人野生型αSyn和3 K突变小鼠中的pS129 +和PK抗性αSyn，与3 K-SKO的水平相似。总之，这些数据进一步验证了SCD作为PD治疗靶标和YTX-7739作为治疗人α-突触核蛋白病的临床候选药物。在线版本包含补充材料，可通过10.1007/s13311-022-01199-7获得。
Increasing evidence has shown that Parkinson’s disease (PD) impairs midbrain dopaminergic, cortical and other neuronal subtypes in large part due to the build-up of lipid- and vesicle-rich α-synuclein (αSyn) cytotoxic inclusions. We previously identified stearoyl-CoA desaturase (SCD) as a potential therapeutic target for synucleinopathies. A brain-penetrant SCD inhibitor, YTX-7739, was developed and has entered Phase 1 clinical trials. Here, we report the efficacy of YTX-7739 in reversing pathological αSyn phenotypes in various in vitro and in vivo PD models. In cell-based assays, YTX-7739 decreased αSyn-mediated neuronal death, reversed the abnormal membrane interaction of amplified E46K (“3K”) αSyn, and prevented pathological phenotypes in A53T and αSyn triplication patient-derived neurospheres, including dysregulated fatty acid profiles and pS129 αSyn accumulation. In 3K PD-like mice, YTX-7739 crossed the blood–brain barrier, decreased unsaturated fatty acids, and prevented progressive motor deficits. Both YTX-7739 treatment and decreasing SCD activity through deletion of one copy of the SCD1 gene (SKO) restored the physiological αSyn tetramer-to-monomer ratio, dopaminergic integrity, and neuronal survival in 3K αSyn mice. YTX-7739 efficiently reduced pS129 + and PK-resistant αSyn in both human wild-type αSyn and 3K mutant mice similar to the level of 3K-SKO. Together, these data provide further validation of SCD as a PD therapeutic target and YTX-7739 as a clinical candidate for treating human α-synucleinopathies. The online version contains supplementary material available at 10.1007/s13311-022-01199-7.
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影响因子：
4.5
作者：
Do CB;Tung JY;Dorfman E;Kiefer AK;Drabant EM;Francke U;Mountain JL;Goldman SM;Tanner CM;Langston JW;Wojcicki A;Eriksson N
通讯作者：
Eriksson N
影响因子：
14.5
作者：
Blauwendraat, Cornelis;Reed, Xylena;Singleton, Andrew B.
通讯作者：
Singleton, Andrew B.
影响因子：
2.7
作者：
Atkinson, Karen A.;Beretta, Elena E.;Trilles, Richard
通讯作者：
Trilles, Richard
DOI：
10.1126/science.1245296
发表时间：
2013-11-22
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Chung CY;Khurana V;Auluck PK;Tardiff DF;Mazzulli JR;Soldner F;Baru V;Lou Y;Freyzon Y;Cho S;Mungenast AE;Muffat J;Mitalipova M;Pluth MD;Jui NT;Schüle B;Lippard SJ;Tsai LH;Krainc D;Buchwald SL;Jaenisch R;Lindquist S
通讯作者：
Lindquist S
帕金森氏病的遗传结构。
DOI：
10.1016/s1474-4422(19)30287-x
发表时间：
2020-02
期刊：
The Lancet. Neurology
影响因子：
--
作者：
Blauwendraat C;Nalls MA;Singleton AB
通讯作者：
Singleton AB