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的最重要领域之一，也是现有的学习和记忆的最佳细胞模型之一。海马是一种大脑结构，对于学习和记忆的存储很重要。已经表明，海马有一个地区，即使在成人生活中，新神经元也出生了。新神经元集成到现有网络中，对于发展新技能和记忆很重要。最近，它还出现了，记忆和学习技能被“存储”在树突状棘中，像神经细胞的树突上的蘑菇一样。树突状的刺是非常“塑料”，也就是说，它们在短时间内的形状，体积和数量都有显着变化。由于棘突主要包含肌动蛋白细胞骨架，因此它们是动态的，大多数棘突能够在肌动蛋白重塑后几秒钟内改变其形状。新的经验和学习导致新刺的形成。已经观察到，畸形的棘或脊柱数量可能与学习障碍有关。此外，出现了纤毛/睫状蛋白与成人神经发生之间的令人兴奋的联系。纤毛是细胞膜的类似头发的投影。它们几乎在所有真核细胞上都发现。在过去的十年中，它已经显示出正常的人类功能，例如能够看到，听到，闻到，呼吸，排泄，繁殖的能力取决于正确的睫状功能。还表明，纤毛对于诸如学习和记忆之类的正常脑功能很重要。正常的纤毛功能取决于包括BBS在内的许多蛋白质的完整性。我们已经产生了初步数据，表明成年新天生神经元的形成以及树突状脊柱数量和密度降低降低了BBS小鼠模型。这些小鼠缺乏功能性的BBS蛋白，因此概括了人类BBS的主要特征，因此，我们将在这里提供我们建议，以研究单个BBS蛋白中的突变如何导致神经可塑性的变化。我们假设缺乏功能齐全的BBS蛋白会影响树突状刺的形成，从而降低了海马的信息存储和有效学习的能力。

项目成果

Loss of Bardet-Biedl syndrome proteins causes synaptic aberrations in principal neurons

• DOI: 10.1101/580399
• 发表时间: 2019-01-01
• 期刊: BioRxiv
• 作者: Haq, N.;Schmidt-Hieber, C.;Christou-Savina, S.
• 通讯作者: Christou-Savina, S.

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