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进行局部决策。在这方面，它们不同于我们身体的任何其他细胞。因此，它们建立了自己独特的地方决策机制。它们还需要在其延伸的不同部分（称为轴突，树突和突触）中做出不同的决定，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种不成熟的信使RNA，这种RNA可以被切割（剪接）成许多不同的版本，它们自己被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，神经元至关重要地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会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节，即隐藏的最后一个外显子（CLE），通常被SFPQ抑制。这种异常剪接事件，通常是以牺牲正常信使RNA为代价实现的，产生稳定的短转录本，能够产生干扰蛋白，完美的候选人携带典型的神经退行性过程的病理。我们的初步研究显示了SFPQ在肌萎缩侧索硬化/额颞叶痴呆（ALS/FTD）神经退行性过程中的关键作用的有力证据。在过去的几个月里，明确的发现表明，SFPQ的丢失是培养中散发性和家族性ALS患者iPSC衍生运动神经元的早期标志，使这种蛋白质成为运动退行性机制的中心。我们正在进行的对新发现的“SFPQ患者”的研究表明，该蛋白可能是更广泛的退行性疾病的核心，包括神经发育综合征。因此，我们建议使用我们独特的模型来了解丢失或突变，SFPQ蛋白在神经元成熟和成人回路中的表达产生了这些CLE转录本，并确定了CLE短转录本对神经元发育的分子和细胞影响。发育和成年神经元。这些对于开发针对神经变性的早期治疗途径，靶向关键致病性克莱斯具有直接重要性。此外，更好地理解CLE-generating新的剪接调控可能对更广泛的剪接依赖性病理学如癌症具有影响。

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.