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.

健康的神经元是很长的细胞，将局部决定远离其细胞体。在这方面，它们与我们身体的任何其他细胞不同。因此，他们建立了当地决策的机制。他们还需要在其扩展的不同部分（称为轴突，树突和突触）中做出不同的决策，为此，能够产生复杂系列蛋白质的表达基因。这些基因正在制造一种未成熟的信使RNA，可以将（拼接）切成许多不同的版本，它们本身转化为不同的蛋白质。当他们通过剪接表达许多成熟的使者时，神经元至关重要地控制这些替代剪接。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10年中，人遗传发现，产生剪接机制的基因中的突变正在引起神经退行性疾病。最近，我们发现了这种剪接因子的必需核和细胞质作用，称为SFPQ在运动电路发育和变性中，发现了一种新型的剪接调控，即通常受SFPQ抑制的隐秘最后一个外显子（CLE）。这个通常以正常信使RNA为代价实现的异常剪接事件，产生稳定的短转录本能够制造干扰蛋白，完美的候选物，以携带典型的神经退行性过程的病理。我们的最初研究表明，有力的证据表明SFPQ在肌萎缩性侧面硬化症/额颞痴呆（ALS/FTD）神经退行性过程中的关键作用。在过去的几个月中，明确的发现表明，SFPQ的丧失是奇异和家族性ALS患者IPSC衍生的运动神经元的早期标志，将这种蛋白质放在运动退化机制的中心。我们正在进行的对新鉴定的“ SFPQ患者”的研究表明，该蛋白质可能是更广泛的变性疾病的核心，包括神经发育综合性综合征。关于发展和成人神经元。这些对于针对神经变性的早期治疗途径至关重要，以关键的致病性cles为目标。此外，更好地了解产生CLE的新型剪接调节可能会对更广泛的剪接依赖性病理（例如癌症）具有影响。

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

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

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