透過分析小鼠行為實驗探討VCP缺陷與自閉症的關聯性;Analysis of behavioral features of VCP mutant mice, a mouse model for autism

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Title:	透過分析小鼠行為實驗探討VCP缺陷與自閉症的關聯性;Analysis of behavioral features of VCP mutant mice, a mouse model for autism
Authors:	林希慈;Lin, Si-Cih
Contributors:	生命科學系
Keywords:	VCP;自閉症;行為實驗;VCP;Autism;behavior
Date:	2019-06-25
Issue Date:	2019-09-03 14:31:59 (UTC+8)
Publisher:	國立中央大學
Abstract:	缬絡胺酸蛋白質（Valosin-containing protein, VCP），又被稱為p97，屬於第二型ATP水解酶，參與許多不同類型的細胞活動。作為一個在細胞中扮演多種角色的伴侶蛋白（chaperone protein），VCP由與其作用的輔因子（cofactor）決定該VCP複合物的細胞功能，受VCP調控的細胞功能包括：內質網的蛋白降解（ERAD）、泛素-蛋白酶體系統（ubiquitin-proteasome system, UPS）相關的蛋白降解、以及內質網（ER）及高基氏體（Golgi）的膜融合（membrane fusion）等。VCP突變導致的疾病影響多重系統，如：inclusion body myopathy associated with Paget’s disease of bone and frontotemporal dementia (IBMPFD)、漸凍症（amyloid lateral sclerosis, ALS）、泛自閉症障礙（autism spectrum disorder, ASD）。本實驗室之前的研究發現Vcp與其輔因子p47共同調控大鼠海馬迴神經細胞的內質網發育，影響新蛋白的合成效率，最終導致樹突棘（dendritic spine）的密度改變，而白胺酸（Leucine, Leu）已知可以透過mTOR路徑促進蛋白質的合成，額外增加Leu的含量可以改善因Vcp突變導致的樹突棘密度下降，說明蛋白合成在神經發育中扮演重要的角色。本論文的目的是以Vcp+/R95G突變小鼠進行行為實驗，探討蛋白質合成對Vcp+/R95G小鼠的影響。我使用兩種不同蛋白質含量的飼料，餵食Vcp+/R95G小鼠，並以同胎的野生型（wild-type）小鼠為比較。實驗結果顯示，不論餵食高含量或一般蛋白含量的飼料，Vcp+/R95G小鼠與對照組的體重、拉力、活動力、工作記憶、焦慮程度、以及肌肉能力與協調感都沒有顯著差異。然而，我們發現2個月大、餵食一般蛋白含量飼料的Vcp+/R95G小鼠的社交意願下降，而這個社交障礙可以透過餵食高蛋白飼料獲得改善，證明透過飲食提高蛋白質的合成效率，就可以回復因Vcp+/R95G造成的社交意願下降。這些結果說明飲食中的蛋白質在調控神經功能及社交行為的重要性，也為自閉症提供一個新的治療方向。;Valosin-containing protein (VCP, also known as p97) belongs to the family of type Ⅱ ATPase associated with variety of cellular activities (AAA). It functions as a chaperone involved in diverse cellular processes, including endoplasmic reticulum (ER) – associated protein degradation (ERAD), ubiquitin-proteasome system (UPS)-mediated protein degradation, ER and Golgi membrane fusion process. Mutations in the VCP gene cause multisystem disorders, such as inclusion body myopathy associated with Paget’s disease of bone and frontotemporal dementia (IBMPFD), amyloid lateral sclerosis (ALS), and autism spectrum disorder (ASD). Our previous study showed that Vcp and its cofactor p47 regulate ER morphology and protein synthesis efficiency in rat hippocampal neuron, and consequently control dendritic spine density. Leucine supplementation that promotes protein synthesis through mTOR pathway can rescue the reduction of spine density in Vcp+/R95G mutant neurons, suggesting the importance of protein synthesis in neuronal morphology controlled by Vcp. This thesis aims to further investigate the role of protein synthesis in VCP-regulated brain function. Here, I used Vcp+/R95G knock-in mice and wild-type littermates to conduct behavioral assays. Two kinds of diets with different protein content were provided to the mice. The results showed that no matter treated the mice with high or normal protein content diet, Vcp+/R95G mice showed comparable body weight and muscle strength to the wild-type mice, and had no defects in locomotion activity, spatial working memory, and rotarod tests. The anxiety level measured in light-dark box model was not increased in the Vcp+/R95G mice group. Nevertheless, we found that 2-month-old Vcp+/R95G mice fed with normal protein content diet reduced social interaction. In addition, the social deficit can be rescued by treating with high protein content diet. In this study, we demonstrate that raising the protein synthesis efficiency through the diet can improve the reduction of social tendency caused by Vcp+/R95G. These results suggested that protein synthesis plays an important role in regulating neuron function and social behavior, providing a potential therapeutic strategy for ASD treatment.
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