Lentiviral-mediated knock-down of GD3 synthase protects against MPTP-induced motor deficits and neurodegeneration.
Lentiviral-mediated knock-down of GD3 synthase protects against MPTP-induced motor deficits and neurodegeneration.
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DOI：
10.1016/j.neulet.2018.10.038
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发表时间：
2019-01-23
影响因子：
2.5
通讯作者：
McDonald MP
中科院分区：
文献类型：
--
作者：
Dhanushkodi A;Xue Y;Roguski EE;Ding Y;Matta SG;Heck D;Fan GH;McDonald MP
越来越多的证据表明神经节苷脂在脑功能和神经退行性疾病中发挥重要作用。外源性GM 1具有广泛的神经保护作用，包括在帕金森病的啮齿动物、猫科动物和灵长类动物模型中，并在临床试验中显示出积极的作用。我们和其他人已经表明，抑制神经节苷脂生物合成酶GD 3合成酶（GD 3S）增加内源性GM 1神经节苷脂水平。我们最近报道了靶向缺失编码GD 3S的基因St 8 sia 1，可预防运动障碍并显著减弱1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）诱导的神经退行性变。本研究探讨了GD 3S抑制对MPTP神经毒性和帕金森病的影响。向小鼠纹状体内注射靶向GD 3S的慢病毒载体介导的shRNA构建体（shGD 3S）或乱序序列对照（scrambled-sequence control，shRNA）。18 mg/kg × 5天的MPTP方案使经siRNA处理的小鼠的黑质丘脑部中的酪氨酸羟化酶阳性神经元减少了近三分之二。在用shGD 3S处理的小鼠中，MPTP诱导的病变大约是该尺寸的一半。MPTP诱导运动迟缓和缺陷的精细运动技能的小鼠与RNA治疗。这些缺陷在shGD 3S处理的小鼠中不存在。这些结果表明，GD 3S的抑制可防止与MPTP给药相关的黑质纹状体损伤、运动迟缓和精细运动技能缺陷。
Converging evidence demonstrates an important role for gangliosides in brain function and neurodegenerative diseases. Exogenous GM1 is broadly neuroprotective, including in rodent, feline, and primate models of Parkinson’s disease, and has shown positive effects in clinical trials. We and others have shown that inhibition of the ganglioside biosynthetic enzyme GD3 synthase (GD3S) increases endogenous levels GM1 ganglioside. We recently reported that targeted deletion of St8sia1, the gene that codes for GD3S, prevents motor impairments and significantly attenuates neurodegeneration induced by 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The current study investigated the effects of GD3S inhibition on the neurotoxicity and parkinsonism induced by MPTP. Mice were injected intrastriatally with a lentiviral-vector-mediated shRNA construct targeting GD3S (shGD3S) or a scrambled-sequence control (scrRNA). An MPTP regimen of 18 mg/kg × 5 days reduced tyrosine-hydroxylase-positive neurons in the substantia nigra pars compacta of scrRNA-treated mice by nearly two-thirds. In mice treated with shGD3S the MPTP-induced lesion was approximately half that size. MPTP induced bradykinesia and deficits in fine motor skills in mice treated with scrRNA. These deficits were absent in shGD3S-treated mice. These results suggest that inhibition of GD3S protects against the nigrostriatal damage, bradykinesia, and fine-motor-skill deficits associated with MPTP administration.
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影响因子：
3.6
作者：
Casas, M;Prat, G;Jané, F
通讯作者：
Jané, F
影响因子：
5.1
作者：
Carpentier, D. C. J.;Vevis, K.;Mazarakis, N. D.
通讯作者：
Mazarakis, N. D.
影响因子：
5.3
作者：
Cearley, Cassia N.;Wolfe, John H.
通讯作者：
Wolfe, John H.
DOI：
10.1111/gbb.12377
发表时间：
2017-06
期刊：
Genes, brain, and behavior
影响因子：
--
作者：
Akkhawattanangkul Y;Maiti P;Xue Y;Aryal D;Wetsel WC;Hamilton D;Fowler SC;McDonald MP
通讯作者：
McDonald MP
影响因子：
4.2
作者：
Bernardo, Alexandra;Harrison, Fiona E.;McDonald, Michael P.
通讯作者：
McDonald, Michael P.