Defining the role of ciliary BBS proteins in neuroplasticity

定义睫状 BBS 蛋白在神经可塑性中的作用

• 批准号: BB/M020991/1
• 负责人: Philip Beales
• 金额: $ 60.32万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FM020991%2F1
• 关键词: Defining; role; ciliary; BBS; proteins

Neuronal plasticity is among the most important areas of modern neuroscience research and one of the best existing cellular models for learning and memory. The hippocampus is a brain structure important for learning and the storage of memories. It has been shown that there is an area in hippocampus where new neurons are born even during adult life. New neurons integrate into existing networks and are important for developing new skills and memory. It has also recently emerged that memories and learning skills are "stored" in dendritic spines, mushroom like protrusions on the dendrites of nerve cells. Dendritic spines are very "plastic", that is, they change significantly in shape, volume, and number over a short time course. Because spines mostly comprise an actin cytoskeleton, they are dynamic, with the majority of spines able to change their shape within seconds to minutes following actin remodelling. New experiences and learning lead to the formation of new spines. It has been observed that malformed spines or reduced spine number can be associated with learning disabilities.Recently, an exciting link between cilia/ciliary proteins and adult neurogenesis has emerged. Cilia are hair-like projections from the cell membrane. They are found on almost all eukaryotic cells. In the last decade it has been shown normal human functions such as ability to see, hear, smell, breathe, excrete, reproduce critically depend on correct ciliary function. It has been also shown that cilia are important for normal brain functions such as learning and memory. Normal cilia function depends on integrity of many proteins including BBS. We have generated preliminary data indicating that there is a reduction in formation of adult new born neurons as well as reduction in dendritic spine number and density in Bbs mice model. These mice lack a functional BBS protein and therefore recapitulates the main features of human BBS and thus, will provide Here we propose to investigate how mutation in a single BBS protein might lead to the changes in neuroplasticity. We hypothesise that the absence of a fully functioning Bbs protein affects the formation of dendritic spines thus reducing the hippocampal capacity for information storage and effective learning.

神经元可塑性是现代神经科学研究中最重要的领域之一，也是目前最好的学习和记忆细胞模型之一。海马体是一个对学习和记忆储存很重要的大脑结构。研究表明，即使在成年后，海马体中也有一个区域会产生新的神经元。新的神经元整合到现有的网络中，对于发展新技能和记忆非常重要。最近还发现，记忆和学习技能被“储存”在树突棘中，树突棘是神经细胞树突上的蘑菇状突起。树突棘具有很强的“可塑性”，也就是说，它们的形状、体积和数量在短时间内会发生显著变化。由于脊柱大多由肌动蛋白细胞骨架组成，因此它们是动态的，大多数脊柱能够在肌动蛋白重塑后的几秒钟到几分钟内改变形状。新的经验和学习导致新脊柱的形成。据观察，脊柱畸形或脊柱数量减少可能与学习障碍有关。最近，一个令人兴奋的纤毛/纤毛蛋白与成人神经发生之间的联系已经出现。纤毛是从细胞膜上伸出的毛发状突起。它们几乎存在于所有真核细胞中。在过去的十年中，人们发现正常的人类功能，如视觉、听觉、嗅觉、呼吸、排泄、繁殖等，都严重依赖于纤毛的正常功能。研究还表明，纤毛对学习和记忆等正常大脑功能也很重要。正常纤毛功能依赖于包括BBS在内的许多蛋白质的完整性。我们已经产生了初步的数据表明，在Bbs小鼠模型中，成年新生神经元的形成减少，树突棘的数量和密度也减少。这些小鼠缺乏功能性BBS蛋白，因此概括了人类BBS的主要特征，因此，我们建议研究单个BBS蛋白的突变如何导致神经可塑性的变化。我们假设缺乏功能完整的Bbs蛋白会影响树突棘的形成，从而降低海马信息存储和有效学习的能力。

项目成果

Common genetic variation drives molecular heterogeneity in human iPSCs.

• DOI: 10.1038/nature22403
• 发表时间: 2017-06-15
• 期刊: Nature
• 影响因子: 64.8
• 作者: Kilpinen H;Goncalves A;Leha A;Afzal V;Alasoo K;Ashford S;Bala S;Bensaddek D;Casale FP;Culley OJ;Danecek P;Faulconbridge A;Harrison PW;Kathuria A;McCarthy D;McCarthy SA;Meleckyte R;Memari Y;Moens N;Soares F;Mann A;Streeter I;Agu CA;Alderton A;Nelson R;Harper S;Patel M;White A;Patel SR;Clarke L;Halai R;Kirton CM;Kolb-Kokocinski A;Beales P;Birney E;Danovi D;Lamond AI;Ouwehand WH;Vallier L;Watt FM;Durbin R;Stegle O;Gaffney DJ
• 通讯作者: Gaffney DJ