TARGETING PARKIN & MITOCHONDRIAL DYNAMICS IN HUNTINGTON'S DISEASE

瞄准帕金

• 批准号: MR/M013847/1
• 负责人: Flaviano Giorgini
• 金额: $ 55.49万
• 依托单位: University of Leicester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 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%2FM013847%2F1
• 关键词: TARGETING; PARKIN; MITOCHONDRIAL; DYNAMICS; HUNTINGTON

Huntington's disease is an incurable, fatal neurodegenerative disorder that is characterised by the loss of vulnerable neurons in the brains of patients. The disease is caused by an increase in the size of a particular DNA sequence (a trinucleotide CAG repeat) which encodes for the amino acid glutamine in the huntingtin (HTT) gene. If the number of glutamines in the HTT protein increases beyond a critical length it misfolds and forms protein tangles, which can disrupt vital cellular processes. An increased number of CAG repeat units in the HTT gene is associated with an earlier age of Huntington's onset. However, there is substantial variability in the onset of symptoms in individuals with the same number of repeats, and studies have shown that ~40 % of this variation is due to other genes. This suggests that there are many potential therapeutic targets capable of significantly altering age of disease onset in the human genome.Previous work by our laboratory and others has found that mitochondria - the energy powerhouses of cells - do not function properly in several ways in Huntington's disease. Interestingly, we have recently found that the protein parkin, which is critical for clearing unhealthy mitochondria for the cell, can improve disease symptoms in a fruit fly model of Huntington's. Notably, mutations in the gene encoding parkin cause hereditary forms of Parkinson's disease. Here we propose to dissect the mechanisms underlying parkin protection. As parkin is involved in controlling the shape of mitochondria, we will interrogate mitochondrial morphology using various microscopy-based techniques, in order to see if in the context of Huntington's model flies parkin influences this process. In parallel, we will also study mitochondrial function in these flies using several biochemical approaches. We will also extend this work to systematically test several proteins related to parkin function and mitochondrial dynamics, in order to better understand how parkin is influencing disease "symptoms" in Huntington's flies. In total, this work will inform the mechanisms underlying Huntington's disease, will may ultimately lead to the development of novel therapeutic strategies for this disorder. As mitochondrial dysfunction is linked to several neurodegenerative diseases, any compelling insights may ultimately have broader significance.

亨廷顿舞蹈症是一种无法治愈的致命性神经退行性疾病，其特征是患者大脑中脆弱神经元的丧失。该疾病是由编码亨廷顿蛋白 (HTT) 基因中的氨基酸谷氨酰胺的特定 DNA 序列（三核苷酸 CAG 重复序列）大小增加引起的。如果 HTT 蛋白中谷氨酰胺的数量增加超过临界长度，它就会错误折叠并形成蛋白缠结，从而破坏重要的细胞过程。 HTT 基因中 CAG 重复单位数量的增加与亨廷顿舞蹈病发病年龄较早有关。然而，具有相同重复次数的个体中症状的出现存在很大差异，研究表明约 40% 的这种差异是由其他基因造成的。这表明人类基因组中存在许多能够显着改变疾病发病年龄的潜在治疗靶点。我们实验室和其他人之前的工作发现，线粒体（细胞的能量发源地）在亨廷顿舞蹈病中以多种方式无法正常发挥作用。有趣的是，我们最近发现蛋白质parkin对于清除细胞中不健康的线粒体至关重要，可以改善亨廷顿舞蹈症果蝇模型的疾病症状。值得注意的是，帕金蛋白编码基因的突变会导致遗传性帕金森病。在这里，我们建议剖析 Parkin 保护的机制。由于帕金参与控制线粒体的形状，我们将使用各种基于显微镜的技术来询问线粒体形态，以便看看在亨廷顿模型果蝇的背景下帕金是否影响这一过程。与此同时，我们还将使用几种生化方法研究这些果蝇的线粒体功能。我们还将扩展这项工作，系统地测试与帕金功能和线粒体动力学相关的几种蛋白质，以便更好地了解帕金如何影响亨廷顿果蝇的疾病“症状”。总的来说，这项工作将揭示亨廷顿病的潜在机制，并可能最终导致针对这种疾病的新治疗策略的开发。由于线粒体功能障碍与多种神经退行性疾病有关，任何令人信服的见解最终都可能具有更广泛的意义。

项目成果

Visualization of Mutant Aggregates from Clock Neurons by Agarose Gel Electrophoresis (AGERA) in Drosophila melanogaster.

• DOI: 10.1007/978-1-0716-2249-0_25
• 发表时间: 2022-01-01
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Delfino, Laura;Campesan, Susanna;Rosato, Ezio
• 通讯作者: Rosato, Ezio

Bypassing mitochondrial defects rescues Huntington's phenotypes in Drosophila

• DOI: 10.1016/j.nbd.2023.106236
• 发表时间: 2023-07-28
• 期刊: NEUROBIOLOGY OF DISEASE
• 影响因子: 6.1
• 作者: Campesan，Susanna;del Popolo，Ivana;Giorgini，Flaviano
• 通讯作者: Giorgini，Flaviano

Partial loss of MCU mitigates pathology in vivo across a diverse range of neurodegenerative disease models.

MCU 的部分缺失可减轻多种神经退行性疾病模型的体内病理学。

• DOI: 10.1016/j.celrep.2024.113681
• 发表时间: 2024
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Twyning MJ

Nitric oxide-mediated posttranslational modifications control neurotransmitter release by modulating complexin farnesylation and enhancing its clamping ability.

• DOI: 10.1371/journal.pbio.2003611
• 发表时间: 2018-04
• 期刊: PLoS biology
• 影响因子: 9.8
• 作者: Robinson SW;Bourgognon JM;Spiers JG;Breda C;Campesan S;Butcher A;Mallucci GR;Dinsdale D;Morone N;Mistry R;Smith TM;Guerra-Martin M;Challiss RAJ;Giorgini F;Steinert JR
• 通讯作者: Steinert JR

A novel role for kynurenine 3-monooxygenase in mitochondrial dynamics.

• DOI: 10.1371/journal.pgen.1009129
• 发表时间: 2020-11
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Maddison DC;Alfonso-Núñez M;Swaih AM;Breda C;Campesan S;Allcock N;Straatman-Iwanowska A;Kyriacou CP;Giorgini F
• 通讯作者: Giorgini F