Investigating deficits of axonal RNA metabolism and axonal signalling in amyotrophic lateral sclerosis

研究肌萎缩侧索硬化症中轴突 RNA 代谢和轴突信号传导的缺陷

• 批准号: MR/M008606/1
• 负责人: Pietro Fratta
• 金额: $ 147.32万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 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=MR%2FM008606%2F1
• 关键词: Investigating; deficits; axonal; RNA; metabolism

Amyotrophic Lateral Sclerosis (ALS), also known as motor neuron disease (MND), is a devastating neurodegenerative disorder which causes progressive loss of muscle function and paralysis. ALS is incurable and leads to death, usually caused by the inability to breathe, on average only 3 years after diagnosis, with a lifetime risk of about 1 in 400. The main cells affected in this disease are nerve cells called motor neurons (MNs), which progressively die during the course of ALS. MNs are amongst the largest cells of the body and connect the brain and the spinal cord to the muscles therefore making movement possible. In order to do this, MNs rely on one thin process, named the axon, which extends from the spinal cord out to each and every muscle of our body. In adults, a single axon can measure over a meter, running from the spinal cord to our fingers or toes, and needs sophisticated transport and communication systems to survive and function. Importantly, research has shown that abnormalities in axons are found in the very early stages of ALS and other incurable human diseases. All cells in an individual's body, although very diverse from each other, contain the same genetic material called DNA, that gives instructions to each individual cell. Therefore the identity of each cell type (whether a MN or a heart cell, for example) is the result of which portions of DNA are active and produce another type of chemical called RNA. RNA carries all the necessary information for the cell to function. The sum of all the RNA in a cell, named the transcriptome, is the signature that characterises each cell type. Knowing the transcriptome of a certain cell type provides insights into its biology and helps determine the causes of diseases. This is particularly relevant with MNs in ALS since there is good evidence showing that the biological processes linked to RNA 'metabolism' are primarily affected in ALS.Further, RNA is transported in axons and this is essential for axon maintenance and its response to injuries. The findings summarized above, highlighting that: 1) axons are involved in early stages of disease; and 2) ALS is caused by alterations of the RNA repertoire in MNs, alongside with novel preliminary data from my Sponsor's laboratory which shows that 3) key ALS molecules localise to cellular organelles which are involved in the communication system of axons, all converge to form my research questions.I will use a novel animal model of ALS to investigate: a) Which changes occur in the RNA of axons; b) How these changes can play a role in ALS; c) How the communication system between axons and the cell body is affected in ALS. The feasibility of this project is ensured by the recent technological advances provided by my Sponsor's laboratory and collaborators. These cutting edge approaches will allow me to isolate and study RNA specifically found in MNs and their axons. Further, I will be able to isolate the small particles that contribute to transmitting survival signals in MN axons. In summary this project will contribute to understand how axons function normally and what goes wrong in ALS. This will greatly help us to understand disease mechanisms and discover novel targets for effective therapies for ALS.

肌萎缩侧索硬化症（ALS），也称为运动神经元疾病（MND），是一种破坏性的神经退行性疾病，其导致肌肉功能的进行性丧失和瘫痪。ALS是无法治愈的，并导致死亡，通常是由无法呼吸引起的，平均诊断后仅3年，终生风险约为1/400。这种疾病中受影响的主要细胞是称为运动神经元（MN）的神经细胞，它们在ALS过程中逐渐死亡。MN是身体最大的细胞之一，将大脑和脊髓连接到肌肉，因此使运动成为可能。为了做到这一点，MN依赖于一个薄的过程，称为轴突，它从脊髓延伸到我们身体的每一块肌肉。在成年人中，单个轴突可以测量超过一米，从脊髓到我们的手指或脚趾，需要复杂的运输和通信系统才能生存和发挥作用。 重要的是，研究表明，在ALS和其他无法治愈的人类疾病的早期阶段就发现了轴突的异常。一个人体内的所有细胞，尽管彼此非常不同，但都含有相同的遗传物质，称为DNA，它为每个细胞提供指令。因此，每种细胞类型的身份（例如，无论是MN还是心脏细胞）都是DNA部分活跃并产生另一种称为RNA的化学物质的结果。RNA携带细胞功能所需的所有信息。细胞中所有RNA的总和，称为转录组，是表征每种细胞类型的特征。了解某种细胞类型的转录组可以深入了解其生物学，并有助于确定疾病的原因。这与ALS中的MN特别相关，因为有很好的证据表明，与RNA“代谢”相关的生物过程在ALS中主要受到影响。此外，RNA在轴突中转运，这对于轴突维持及其对损伤的反应至关重要。以上总结的发现强调：1）轴突参与疾病的早期阶段;和2）ALS是由MN中RNA库的改变引起的，以及来自我的赞助者实验室的新的初步数据，其显示3）关键ALS分子定位于参与轴突通信系统的细胞器，所有这些都汇聚成我的研究问题。我将使用一种新的ALS动物模型来研究：a）轴突RNA发生了哪些变化; B）这些变化如何在ALS中发挥作用; c）轴突和细胞体之间的通讯系统如何在ALS中受到影响。我的赞助商实验室和合作者提供的最新技术进步确保了该项目的可行性。这些尖端的方法将使我能够分离和研究在MN及其轴突中特别发现的RNA。此外，我将能够分离出有助于在MN轴突中传递生存信号的小颗粒。 总之，这个项目将有助于了解轴突是如何正常工作的，以及ALS中出现了什么问题。这将极大地帮助我们了解疾病机制，并发现有效治疗ALS的新靶点。

项目成果

FUS-ALS mutants alter FMRP phase separation equilibrium and impair protein translation.

• DOI: 10.1126/sciadv.abf8660
• 发表时间: 2021-07
• 期刊: Science advances
• 影响因子: 13.6
• 作者: Birsa N;Ule AM;Garone MG;Tsang B;Mattedi F;Chong PA;Humphrey J;Jarvis S;Pisiren M;Wilkins OG;Nosella ML;Devoy A;Bodo C;de la Fuente RF;Fisher EMC;Rosa A;Viero G;Forman-Kay JD;Schiavo G;Fratta P
• 通讯作者: Fratta P

HnRNP K mislocalisation is a novel protein pathology of frontotemporal lobar degeneration and ageing and leads to cryptic splicing.

• DOI: 10.1007/s00401-021-02340-0
• 发表时间: 2021-10
• 期刊: Acta neuropathologica
• 影响因子: 12.7
• 作者: Bampton A;Gatt A;Humphrey J;Cappelli S;Bhattacharya D;Foti S;Brown AL;Asi Y;Low YH;Foiani M;Raj T;Buratti E;Fratta P;Lashley T
• 通讯作者: Lashley T

The role of hnRNPs in frontotemporal dementia and amyotrophic lateral sclerosis.

• DOI: 10.1007/s00401-020-02203-0
• 发表时间: 2020-11
• 期刊: Acta neuropathologica
• 影响因子: 12.7
• 作者: Bampton A;Gittings LM;Fratta P;Lashley T;Gatt A
• 通讯作者: Gatt A

Corrigendum: Neuregulin 1 type III improves peripheral nerve myelination in a mouse model of congenital hypomyelinating neuropathy.

勘误表：Neuregulin 1 III 型可改善先天性低髓鞘神经病小鼠模型的周围神经髓鞘形成。

• DOI: 10.1093/hmg/ddz037
• 发表时间: 2019
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Belin,Sophie;Ornaghi,Francesca;Shackleford,Ghjuvan'Ghjacumu;Wang,Jie;Scapin,Cristina;Lopez-Anido,Camila;Silvestri,Nicholas;Robertson,Neil;Williamson,Courtney;Ishii,Akihiro;Taveggia,Carla;Svaren,John;Bansal,Rashmi;Schwab,MarkusH
• 通讯作者: Schwab,MarkusH