Brain Glycogen - Metabolism, Mechanisms, and Therapeutic Potential

脑代谢是生物学和人类疾病的一个基本方面。大脑主要依赖于 葡萄糖，消耗大量作为认知，记忆和行为的生化燃料。基本 大脑代谢的各个方面已经得到了广泛的研究，但最近的证据表明， 神经系统疾病中的葡萄糖和糖原代谢最近开辟了新的研究途径。 已深入研究的异常葡萄糖代谢的神经系统疾病是Lafora病 （LD）。LD是一种常染色体隐性遗传、致死性糖原累积病（GSD），男女发病率相同。 症状出现在青春期与抗药性癫痫，共济失调，神经变性，并迅速下降 变成植物人几个实验室使用多种模型的结果表明， 异常的细胞内糖原样聚集体（称为葡聚糖体（PGB））是LD的原因。 引人注目的是，我们和其他人已经在多种神经系统疾病中发现了PGB，我们假设， PGB是大脑影响GSD的疾病进展的驱动力，PGB也发挥着重要作用。 在阿尔茨海默病（AD）中的关键作用。 我们已经对LD中的葡萄糖代谢低下做出了基础性的发现， 影响细胞过程，开发尖端工具来确定潜在的细胞机制， 建立了抑制和/或消除PGB的治疗平台。定义糖原的机制 LD的代谢提供了对PGB如何形成和影响大脑稳态的见解。因此，LD提供了 这是了解正常大脑葡萄糖代谢和更广泛疾病影响的独特窗口， 新陈代谢受到干扰。 这个R35将联合收割机我们的NINDS资助的，LD为中心的R 01和P01，并将我们的专业知识扩展到大脑， 影响GSD并确定PGB在AD中的作用。展望未来，我们将进一步定义LD驱动 干扰信号在分子水平上，阐明细胞生理学的变化，并建立新的 在生物体水平上的治疗方法。令人兴奋的是，关于LD的工作可以作为如何 询问涉及PGB的其他神经系统疾病中的脑代谢扰动。我们将应用这些 强大的LD开发的工具和见解，以确定PGB如何影响多种神经系统疾病， 确定影响疾病进展的糖原中心分子机制，并确定PGB如何 作为临床前治疗，移除影响脑代谢。重要的是，我们有初步的关键部分， 来自小鼠模型和患者组织的LD、脑影响的GSD和AD的数据。增加的 R35所提供的稳定性、自由度和灵活性将使我们能够在大脑中做出开创性的发现 代谢，并确定PGBs在多种疾病中的作用，同时进行发展的关键步骤， 治疗和生物标志物开发。 !

Brain metabolism is a fundamental aspect of biology and human disease. The brain critically depends on glucose, consuming large quantities as the biochemical fuel for cognition, memory, and behavior. Fundamental aspects of brain metabolism have been extensively studied, but recent evidence regarding the key role of glucose and glycogen metabolism in neurological diseases has recently opened up new avenues of research. The neurological disease where aberrant glucose metabolism has been investigated in-depth is Lafora disease (LD). LD is an autosomal recessive, fatal, glycogen storage disease (GSD) that equally affects both sexes. Symptoms emerge in adolescence with drug-resistant epilepsy, ataxia, neurodegeneration, and a rapid decline into a vegetative state before death. Results from several labs using multiple models have demonstrated that aberrant intracellular glycogen-like aggregates, known as polyglucosan bodies (PGBs), are the cause of LD. Strikingly, we and others have identified PGBs in multiple neurological diseases and we hypothesize that PGBs are a driving force in disease progression for brain-impacted GSDs, and that PGBs also play a critical role in Alzheimer’s disease (AD). We have made foundational discoveries regarding glucose hypometabolism in LD, defined how PGBs impact cellular processes, developed cutting-edge tools to determine the underlying cellular mechanisms, and established therapeutic platforms to inhibit and/or eliminate PGBs. Defining the mechanisms of glycogen metabolism in LD provides insights into how PGBs form and impact brain homeostasis. Thus, LD offers a unique window into both normal brain glucose metabolism and broader disease implications when this metabolism is perturbed. This R35 will combine our NINDS-funded, LD-centric R01 and P01, and extend our expertise to brain- impacted GSDs and determining the role of PGBs in AD. Moving forward, we will further define LD-driven perturbations in signaling at the molecular level, elucidate changes in cellular physiology, and establish novel therapeutic modalities at the organismal level. Excitingly, the work on LD serves as a model for how to interrogate brain metabolic perturbations in other neurological diseases involving PGBs. We will apply these powerful LD-developed tools and insights to define how PGBs impact multiple neurological diseases, determine the glycogen-centric molecular mechanisms impacting disease progression, and define how PGB removal affects brain metabolism as a pre-clinical therapeutic. Importantly, we have key pieces of preliminary data for LD, brain-impacted GSDs, and AD from both mouse models and patient tissue. The increased stability, freedom, and flexibility provided by the R35 would allow us to make seminal discoveries in brain metabolism and define the role of PGBs in multiple diseases while carrying out key steps in the development of therapies and biomarker development. !