Post-transcriptional regulation in motor and cognitive disorders

运动和认知障碍的转录后调节

• 批准号: MR/T033126/1
• 负责人: Corinne Houart
• 金额: $ 100.12万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT033126%2F1
• 关键词: Post; transcriptional; regulation; motor; cognitive

Healthy neurons are very long cells, taking local decisions far away from their cell body. They are in this respect different from any other cell of our body. For this reason, they have built mechanisms of local decision-making unique to them. They also need to take different decisions in different parts of their extensions (called axons, dendrites and synapses) and for this, express genes that are able to produce a complex series of proteins. These genes are making one immature messenger RNA that can be cut (splicing) into many different versions, themselves translated into different proteins. As they are expressing many mature messengers by splicing, the neurons crucially need to control these alternative splicing. Problems in achieving these events are giving severe problems to the neurons. In the past 10 years, human genetic discovered that mutations in genes producing the splicing machinery are causing neurodegenerative disorders. We recently discovered the essential nuclear and cytoplasmic roles of such splicing factor, called SFPQ in motor circuit development and degeneration and found a novel type of splicing regulation, the cryptic last exon (CLE), normally repressed by SFPQ. This aberrant splicing event, often achieved at the expense of the normal messenger RNAs, produces stable short transcripts able to make interfering proteins, perfect candidates to carry pathologies typical of neurodegenerative processes. Our initial study showed strong evidence for a key role of SFPQ in Amyotrophic Lateral Sclerosis/Fronto-temporal dementia (ALS/FTD) neurodegenerative processes. In the past months, unambiguous findings show that loss of SFPQ is an early hallmark across sporadic and familial ALS patient iPSC-derived motor neurons in culture, putting this protein at the centre of motor degenerative mechanisms. Our ongoing studies of newly identified "SFPQ patients" indicates that the protein is likely to be at the core of a wider variety of degenerative disorders, including neurodevelopmental syndromes.We therefore propose to use our unique models to understand how loss, or mutations, of SFPQ protein during neuronal maturation and in adult circuits generates these CLE transcripts and identify the molecular and cellular consequence of CLE short transcripts on developing and adult neurons. These are of direct importance to develop early therapeutic avenues against neurodegeneration, targeting key pathogenic CLEs. In addition, better understand the CLE-generating novel splicing regulation is likely to have implications on a wider set of splicing-dependent pathologies such as cancers.

健康的神经元是非常长的细胞，在远离细胞体的地方做出局部决策。在这方面，它们与我们身体的任何其他细胞不同。为此，他们建立了自己特有的地方决策机制。它们还需要在其延伸的不同部分（称为轴突、树突和突触）做出不同的决定，为此，表达能够产生一系列复杂蛋白质的基因。这些基因正在制造一种不成熟的信使RNA，它可以被切割（剪接）成许多不同的版本，它们本身可以翻译成不同的蛋白质。由于神经元通过剪接表达许多成熟的信使，因此神经元迫切需要控制这些选择性剪接。实现这些事件的问题给神经元带来了严重的问题。在过去的十年里，人类遗传学发现，产生剪接机制的基因突变正在导致神经退行性疾病。我们最近发现了这种剪接因子（称为 SFPQ）在运动回路发育和变性中的重要核和细胞质作用，并发现了一种新型剪接调节，即神秘的最后外显子（CLE），通常受到 SFPQ 抑制。这种异常剪接事件通常以正常信使 RNA 为代价来实现，产生稳定的短转录本，能够产生干扰蛋白，是携带神经退行性过程典型病理的完美候选者。我们的初步研究表明，SFPQ 在肌萎缩侧索硬化症/额颞叶痴呆 (ALS/FTD) 神经退行性过程中发挥着关键作用。在过去的几个月中，明确的研究结果表明，SFPQ 的丧失是培养中散发性和家族性 ALS 患者 iPSC 衍生的运动神经元的早期标志，使这种蛋白质处于运动退行性机制的中心。我们对新发现的“SFPQ 患者”正在进行的研究表明，该蛋白质可能是更广泛的退行性疾病（包括神经发育综合征）的核心。因此，我们建议使用我们独特的模型来了解 SFPQ 蛋白的缺失或突变是如何发生的。 SFPQ 蛋白在神经元成熟期间和成体回路中生成这些 CLE 转录本，并识别 CLE 短转录本对发育中和成体神经元的分子和细胞后果。这些对于开发针对关键致病性 CLE 的神经退行性疾病早期治疗途径具有直接重要意义。此外，更好地理解产生 CLE 的新型剪接调控可能会对更广泛的剪接依赖性病理学（例如癌症）产生影响。

项目成果

Prematurely terminated intron-retaining mRNAs invade axons in SFPQ null-driven neurodegeneration and are a hallmark of ALS.

• DOI: 10.1038/s41467-022-34331-4
• 发表时间: 2022-11-22
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Taylor, Richard;Hamid, Fursham;Fielding, Triona;Gordon, Patricia M.;Maloney, Megan;Makeyev, Eugene, V;Houart, Corinne
• 通讯作者: Houart, Corinne

A conserved role for the ALS-linked splicing factor SFPQ in repression of pathogenic cryptic last exons.

• DOI: 10.1038/s41467-021-22098-z
• 发表时间: 2021-03-26
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Gordon PM;Hamid F;Makeyev EV;Houart C
• 通讯作者: Houart C

Identification of a novel interaction of FUS and syntaphilin may explain synaptic and mitochondrial abnormalities caused by ALS mutations.

• DOI: 10.1038/s41598-021-93189-6
• 发表时间: 2021-06-30
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Salam S;Tacconelli S;Smith BN;Mitchell JC;Glennon E;Nikolaou N;Houart C;Vance C
• 通讯作者: Vance C

The zinc finger/RING domain protein Unkempt regulates cognitive flexibility.

• DOI: 10.1038/s41598-021-95286-y
• 发表时间: 2021-08-11
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Vinsland E;Baskaran P;Mihaylov SR;Hobbs C;Wood H;Bouybayoune I;Shah K;Houart C;Tee AR;Murn J;Fernandes C;Bateman JM
• 通讯作者: Bateman JM

Identification of a Novel Interaction of FUS and Syntaphilin May Explain Synaptic and Mitochondrial Abnormalities Caused by ALS Mutations

FUS 和 Syntaphilin 的新型相互作用的鉴定可能解释 ALS 突变引起的突触和线粒体异常

• DOI: 10.21203/rs.3.rs-374611/v2
• 发表时间: 2021
• 作者: Vance C