Cao J K, Viray K, Shin M, Hsu K-L, Mackie K, Westenbroek R, Stella N
Department of Pharmacology, University of Washington School of Medicine, Seattle, WA 98195, USA.
Department of Chemistry, University of Virginia, Charlottesville, VA 22904, USA.
J Neurol Neurol Disord. 2021 Aug;7(1). Epub 2021 Aug 13.
Huntington's Disease is associated with motor behavior deficits that are lessened by few therapeutic options. This preliminary study tested if pharmacological inhibition of α/β-hydrolase domain containing 6 (), a multifunctional enzyme expressed in the striatum, rescues behavioral deficits in HdhQ200/200 mice. Previous work has shown that this model exhibits a reduction in spontaneous locomotion and motor coordination at 8 and 10 months of age, with a more severe phenotype in female mice. Semi-quantitative immunohistochemistry analysis indicated no change in striatal ABHD6 expression at 8 months of age, but a 40% reduction by 10 months in female HdhQ200/200 mice compared to female wild-type () littermates. At 8 months of age, acute ABHD6 inhibition rescued motor coordination deficits in female HdhQ200/200 mice without affecting WT performance. ABHD6 inhibition did not impact spontaneous locomotion, grip strength, or overall weight in either group, showing that effects were specific to motor coordination. At 10 months of age, semi-chronic ABHD6 inhibition by osmotic pump delivery also rescued motor coordination deficits in female HdhQ200/200 mice without affecting female WT littermates. Our preliminary study suggests that ABHD6 inhibition improves motor performance in female HdhQ200/200 mice.
亨廷顿舞蹈症与运动行为缺陷相关，而针对该疾病的治疗选择寥寥无几。本初步研究旨在测试对含α/β水解酶结构域6（ABHD6）进行药理学抑制（ABHD6是一种在纹状体中表达的多功能酶）是否能挽救HdhQ200/200小鼠的行为缺陷。此前的研究表明，该模型在8个月和10个月大时会出现自发运动和运动协调性下降的情况，且雌性小鼠的表型更为严重。半定量免疫组织化学分析表明，8个月大时纹状体ABHD6表达无变化，但与雌性野生型（WT）同窝小鼠相比，10个月大的雌性HdhQ200/200小鼠中ABHD6表达降低了40%。在8个月大时，急性抑制ABHD6可挽救雌性HdhQ200/200小鼠的运动协调缺陷，且不影响野生型小鼠的表现。抑制ABHD6对两组小鼠的自发运动、握力或总体体重均无影响，表明其作用具有运动协调性特异性。在10个月大时，通过渗透泵给药进行半慢性ABHD6抑制也可挽救雌性HdhQ200/200小鼠的运动协调缺陷，且不影响雌性野生型同窝小鼠。我们的初步研究表明，抑制ABHD6可改善雌性HdhQ200/200小鼠的运动表现。
