Mitochondrial dysfunction in Fragile X: Mechanisms and treatments

脆性 X 细胞线粒体功能障碍：机制和治疗

• 批准号: 10735521
• 负责人: THOMAS A JONGENS
• 金额: $ 53.98万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735521
• 关键词: Adult; Animal Model; Behavior; Behavioral; Biguanides; Biochemical; Brain; Case Study; Cells; Clinical; Clinical Trials; Clinical assessments; Cognition; Cognitive; Cyclic AMP; Data; Defect; Development; Drosophila genus; FMR1; Fibroblasts; Fragile X Syndrome; Functional disorder; Genetic; Goals; Homologous Gene; Human; Impaired cognition; Impairment; Insulin; Intellectual functioning disability; Life; Link; Memory; Memory impairment; Metformin; Mitochondria; Modeling; Mus; Neurodevelopmental Disorder; Outcome; Output; Oxidation-Reduction; PGC1a Regulation Pathway; PIK3CG gene; Pathogenesis; Pathway interactions; Patients; Periodicity; Phase II Clinical Trials; Phenocopy; Phenotype; Physiological; Pre-Clinical Model; Reporting; Role; Signal Pathway; Signal Transduction; Stimulation of Cell Proliferation; Symptoms; System; Testing; Work; aged; autism spectrum disorder; behavioral impairment; behavioral phenotyping; cell type; circadian; clinically relevant; cofactor; dFMR1 gene; experimental study; fly; gene function; improved; inhibitor; insulin signaling; loss of function; loss of function mutation; metabolic phenotype; mitochondrial dysfunction; mouse model; mutant; neural; novel; null mutation; pharmacologic; potential biomarker; restoration; skills; social; spatiotemporal; theories; treatment optimization; treatment strategy

Abstract: Fragile X Syndrome (FXS), the most common cause of intellectual disability and autism, is caused by the loss of FMR1 gene function. Drosophila and mouse models of FXS have been developed that are based on loss of function mutations of their respective homologues of FMR1, dfmr1 and Fmr1. These models display several phenotypes that bear similarity to Fragile X patient symptoms. In previous studies, we and others have identified reduced cAMP levels and increased insulin/PI3K signaling as defects in the Fragile X animal model brains. Our work on a Drosophila FXS model demonstrated that restoration of the cAMP deficit, by treatment with PDE4 inhibitors, restores behavior and memory. We have also shown that genetic and pharmacological manipulations that restore normal insulin signaling levels rescue behavioral and memory deficits. Our findings for both pathway defects have been reproduced in the mouse FXS model. Further, we discovered that metformin treatment of the FXS Drosophila model also restores memory and behavior, a finding that too has been replicated in the mouse FXS model. In sum our studies have determined that three seemingly distinct approaches, e.g. increasing cAMP levels, decreasing insulin signaling and metformin treatment can restore behavioral and cognitive phenotypes displayed by the FXS animal models. Importantly two of these findings are being pursued clinically and have given rise to promising results. A novel PDE4 inhibitor, BPN14770, has been tested in a phase II clinical trial with Fragile X adults. The results of this study have shown that treatment with this compound can significantly improve cognitive and life skills in Fragile X adult aged 18 to 45. Also, several case studies of Fragile X patients treated with metformin have reported improvements in cognitive and social domains. These findings have led to the initiation of clinical trials with metformin. Given the clinical relevance of our findings, an important question that we will address in this study is how these three seemingly different approaches act to restore behavior and cognition in a FXS animal model. Our preliminary studies indicate that they converge on improving mitochondrial function. In recent studies we have identified robust mitochondrial deficits displayed by the Drosophila FXS model and FXS patient derived cells. We have also determined that the mitochondrial master regulator PGC-1a is significantly decreased in the Drosophila model and in FXS patient derived cells. Importantly we have determined that the mitochondrial defects and PGC-1a are improved by metformin treatment and the genetic reduction of insulin signaling. We have also demonstrated that independently increasing PGC-1a expression improves mitochondrial function and a behavioral phenotype. In our proposed studies we will perform experiments to verify that the restoration of the signaling pathway defects, as well as metformin treatment increase both PGC-1a expression and mitochondrial function in the Drosophila FXS model and patient derived cells. These studies will help expand our understanding of how to treat Fragile X syndrome most effectively and possibly other neurodevelopmental disorders due to similar pathophysiological defects.

翻译后摘要：脆性X综合征（FXS），智力残疾和自闭症的最常见的原因，是由 FMR 1基因功能丧失。已经开发了FXS的果蝇和小鼠模型，其基于 FMR 1、dfmr 1和Fmr 1各自同源物的功能缺失突变。这些模型显示 与脆性X综合征患者症状相似的几种表型。在以前的研究中，我们和其他人 在脆性X染色体动物模型中，确定cAMP水平降低和胰岛素/PI 3 K信号传导增加为缺陷 大脑我们对果蝇FXS模型的研究表明，通过治疗， 与PDE 4抑制剂，恢复行为和记忆。我们还表明，遗传和药理学 恢复正常胰岛素信号传导水平的操作挽救了行为和记忆缺陷。我们的研究结果 在小鼠FXS模型中再现了这两种途径缺陷。此外，我们发现二甲双胍 对FXS果蝇模型的治疗也恢复了记忆和行为，这一发现也被复制了 在小鼠FXS模型中。总之，我们的研究已经确定，三个看似不同的方法，例如。 增加cAMP水平，降低胰岛素信号传导和二甲双胍治疗可以恢复行为和 FXS动物模型显示的认知表型。重要的是，这些发现中有两个正在进行中。 临床上，并已产生了有希望的结果。一种新的PDE 4抑制剂BPN 14770已经在一个实验室中进行了测试。 脆性X染色体成人的II期临床试验。这项研究的结果表明，用这种化合物治疗 可显著改善18至45岁脆性X成年人的认知和生活技能。此外，一些案例研究， 接受二甲双胍治疗的脆性X患者报告了认知和社交领域的改善。这些 这些发现导致了二甲双胍临床试验的启动。考虑到我们研究结果的临床相关性， 我们将在本研究中解决的重要问题是，这三种看似不同的方法如何发挥作用， 在FXS动物模型中恢复行为和认知。我们的初步研究表明，他们聚集在 改善线粒体功能在最近的研究中，我们已经确定了以下表现出的强大的线粒体缺陷： 果蝇FXS模型和FXS患者衍生的细胞。我们还确定线粒体的主人 在果蝇模型和FXS患者来源的细胞中，PGC-1a调节因子的表达显著降低。重要的 我们已经确定二甲双胍治疗可以改善线粒体缺陷和PGC-1a， 胰岛素信号的遗传减少。我们还证明，独立增加PGC-1a 表达改善线粒体功能和行为表型。在我们提出的研究中，我们将执行 实验验证了信号通路缺陷的恢复，以及二甲双胍治疗 在果蝇FXS模型和患者来源的FXS模型中增加PGC-1a表达和线粒体功能 细胞这些研究将有助于扩大我们对如何最有效地治疗脆性X综合征的理解， 可能是由于类似的病理生理缺陷引起的其他神经发育障碍。