背景:已经提出抑制HDAC6作为一种广泛适用于Charcot-Marie-Tooth病(CMT)的治疗策略。HDAC6的抑制增加了在轴突运输中重要的蛋白质的乙酰化,比如α-微管蛋白和米罗,并且已在使用CMT小鼠模型的一些临床前研究中被证明是有效的。
目标:这里,我们试图通过检测Hdac6基因缺失对携带Gars1人源化门金等位基因(CMT2D型模型)的小鼠的影响来扩展以前的临床前研究.
方法:将Gars1ΔETAQ小鼠饲养到Hdac6基因敲除菌株中,并对由此产生的后代进行临床相关结局评估.
结果:Hdac6的遗传缺失增加了野生型和Gars1ΔETAQ小鼠坐骨神经中的α-微管蛋白乙酰化。然而,在5周龄时进行测试,缺乏Hdac6的Gars1ΔETAQ小鼠的体重没有变化,肌肉萎缩,握力或耐力,坐骨神经运动神经传导速度,复合肌肉动作电位振幅,或周围神经组织病理学与具有完整Hdac6的Gars1ΔETAQ小鼠相比。
结论:我们的结果与先前两项研究的结果不同,这些研究证明了HDAC6抑制剂tubastatinA在CMT2D小鼠模型中的益处。虽然我们不能完全解释不同的结果,我们的结果为在CMT2D中抑制HDAC6的益处提供了一个反例,建议额外的研究是必要的。
BACKGROUND: Inhibition of HDAC6 has been proposed as a broadly applicable therapeutic strategy for Charcot-Marie-Tooth disease (CMT). Inhibition of HDAC6 increases the acetylation of proteins important in axonal trafficking, such as α-tubulin and Miro, and has been shown to be efficacious in several preclinical studies using mouse models of CMT.
OBJECTIVE: Here, we sought to expand on previous preclinical studies by testing the effect of genetic deletion of Hdac6 on mice carrying a humanized knockin allele of Gars1, a model of CMT-type 2D.
METHODS: Gars1ΔETAQ mice were bred to an Hdac6 knockout strain, and the resulting offspring were evaluated for clinically relevant outcomes.
RESULTS: The genetic deletion of Hdac6 increased α-tubulin acetylation in the sciatic nerves of both wild-type and Gars1ΔETAQ mice. However, when tested at 5 weeks of age, the Gars1ΔETAQ mice lacking Hdac6 showed no changes in body weight, muscle atrophy, grip strength or endurance, sciatic motor nerve conduction velocity, compound muscle action potential amplitude, or peripheral nerve histopathology compared to Gars1ΔETAQ mice with intact Hdac6.
CONCLUSIONS: Our results differ from those of two previous studies that demonstrated the benefit of the HDAC6 inhibitor tubastatin A in mouse models of CMT2D. While we cannot fully explain the different outcomes, our results offer a counterexample to the benefit of inhibiting HDAC6 in CMT2D, suggesting additional research is necessary.