Post-transcriptional regulation in motor and cognitive disorders

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定。在这方面，它们与我们身体的任何其他细胞都不同。为此，他们建立了独有的地方决策机制。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，并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个不成熟的信使RNA，它可以被切割(拼接)成许多不同的版本，它们自己翻译成不同的蛋白质。由于它们通过剪接表达许多成熟的信使，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10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称为SFPQ的剪接因子在马达电路发育和退化中的重要核和细胞质作用，并发现了一种新型的剪接调控，即隐蔽的最后外显子(CLE)，通常由SFPQ抑制。这种异常的剪接事件通常是以正常的信使RNA为代价实现的，它产生稳定的短转录本，能够产生干扰蛋白，从而完美地携带神经退化过程中典型的病理变化。我们最初的研究表明，SFPQ在肌萎缩侧索硬化症/额-颞叶痴呆(ALS/FTD)神经退变过程中起着关键作用。在过去的几个月里，明确的研究结果表明，在培养的散发性和家族性ALS患者的IPSC来源的运动神经元中，SFPQ的丢失是一个早期标志，将该蛋白置于运动退化机制的中心。我们正在对新发现的“SFPQ患者”进行的研究表明，该蛋白可能是包括神经发育综合征在内的更广泛种类退行性疾病的核心。因此，我们建议使用我们独特的模型来了解SFPQ蛋白在神经元成熟过程中和在成人电路中如何丢失或突变产生这些CLE转录本，并确定CLE短转录本对发育中的神经元和成年神经元的分子和细胞后果。这些对于开发针对关键致病循环的神经退行性变的早期治疗途径具有直接重要意义。此外，更好地理解CLE产生的新的剪接调控可能会对更广泛的剪接依赖病理，如癌症产生影响。

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.