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.

摘要：脆弱的X综合征（FXS）是智力残疾和自闭症的最常见原因，是由 FMR1基因函数的丧失。已经开发了基于FX的果蝇和小鼠模型 fMR1，DFMR1和FMR1的各自同源物的功能突变丧失。这些模型显示 几种与脆弱的X患者症状相似的表型。在以前的研究中，我们和其他人有 确定降低的营地水平并增加胰岛素/PI3K信号传导是脆弱的X动物模型中的缺陷 大脑。我们在果蝇FXS模型上的工作表明，通过治疗恢复营地赤字 使用PDE4抑制剂，可以恢复行为和记忆。我们还表明遗传和药理 恢复正常胰岛素信号传导水平的操作挽救行为和记忆缺陷。我们的发现 对于这两个途径缺陷，已经在小鼠FXS模型中复制了。此外，我们发现二甲双胍 FXS果蝇模型的处理也恢复了记忆和行为，这一发现也已被复制 在鼠标FXS模型中。总而言之，我们的研究确定了三种看似不同的方法，例如 增加营地水平，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，这些发现中的两个正在追求 在临床上，已经带来了令人鼓舞的结果。一种新型的PDE4抑制剂BPN14770已在A中测试 II期临床试验与脆弱的X成人。这项研究的结果表明，该化合物的治疗 可以显着提高18至45岁脆弱X成人的认知能力和生活技能。此外，几个案例研究 用二甲双胍治疗的脆弱X患者报告了认知和社会领域的改善。这些 调查结果导致了使用二甲双胍进行临床试验的开始。鉴于我们发现的临床相关性， 我们将在这项研究中解决的重要问题是，这三种看似不同的方法如何行动 恢复FXS动物模型中的行为和认知。我们的初步研究表明它们会融合 改善线粒体功能。在最近的研究中，我们确定了由 果蝇FXS模型和FXS患者衍生的细胞。我们还确定线粒体大师 果蝇模型和FXS患者衍生细胞中的调节剂PGC-1A显着降低。重要的是 我们已经确定线粒体缺陷和PGC-1A通过二甲双胍处理和 胰岛素信号传导的遗传还原。我们还证明了独立增加PGC-1A 表达可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 实验以验证信号通路缺陷的恢复以及二甲双胍处理 增加果蝇FXS模型中的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治疗脆弱X综合征的理解，以及 由于类似的病理生理缺陷，可能是其他神经发育障碍。