Neuroprotection by the GUCY2C gut-brain axis in Parkinson's disease

GUCY2C 肠脑轴对帕金森病的神经保护作用

• 批准号: 10740951
• 负责人: SCOTT A WALDMAN
• 金额: $ 42.9万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740951
• 关键词: 1-Methyl-4-phenylpyridinium; Abbreviations; Agonist; Automobile Driving; Behavior; Biogenesis; Brain; Cell Death; Cell Nucleus; Cessation of life; Characteristics; Chronic; Clinical; Colorectal Cancer; Complex; Constipation; Corpus striatum structure; Cyclic GMP; Data; Dementia; Desire for food; Disease; Disease Management; Disease Progression; Dopamine; Drug Targeting; Dyskinetic syndrome; Electron Transport; Endocrine; FDA approved; Fluids and Secretions; Functional disorder; Genetic; Gliosis; Hormone Receptor; Hormones; Hyperphagia; Hypothalamic structure; In Vitro; Inflammation; Inflammatory Bowel Diseases; Injury; Intestines; Knockout Mice; Leptin; Limb structure; Link; Malignant Neoplasms; Mediating; Memory; Midbrain structure; Mitochondria; Modeling; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Obesity; Oral; Outcome; Oxidative Stress Induction; Parkinson Disease; Pathway interactions; Patients; Periodicity; Proteins; Receptor Signaling; Role; Signal Transduction; Small Intestines; Structure; Substantia nigra structure; Symptoms; Syndrome; Therapeutic; Toxic effect; Toxin; Transcription Coactivator; Translating; Tyrosine 3-Monooxygenase; Ventral Tegmental Area; age related neurodegeneration; disorder prevention; disorders of gut-brain interaction; dopaminergic neuron; enterotoxin receptor; gut-brain axis; in vivo; intestinal injury; mitochondrial dysfunction; motor disorder; motor symptom; neuroprotection; neurotoxicity; novel; novel therapeutic intervention; paracrine; pars compacta; pharmacologic; preservation; prevent; receptor; reduce symptoms; response; therapeutic target; uroguanylin

Parkinson’s disease (PD) is the second most common cause of age-related neurodegeneration in the U.S. In PD, mitochondrial dysfunction in midbrain dopamine (DA) neurons in the substantia nigra (SN) induces oxidative stress and cell death. In turn, this neurodegeneration leads to DA depletion, which underlies the motor dysfunction and dementia that are hallmarks of this disease. Current therapies raise DA levels to relieve motor symptoms, but do not prevent neurodegeneration, disease progression, or death. Thus, there is an essential unmet need to develop novel therapeutic strategies that protect DA neurons from degeneration to prevent and treat PD. Guanylyl cyclase C (GUCY2C) is an intestinal receptor for locally-produced hormones that regulate secretion, the basis for approval of the GUCY2C agonist linaclotide to treat constipation. In intestine, this receptor signaling axis also supports mitochondrial biogenesis through the transcriptional coactivator PGC1α, and its disruption produces mitochondrial dysfunction central to the pathophysiology of cancer; inflammatory bowel disease; and toxic injury. Recently, the GUCY2C hormone axis emerged as the afferent limb of endocrine pathways controlling two discreet circuits in brain. GUCY2C in neurons in the hypothalamic ventral premammillary nucleus controls leptin signaling regulating appetite. Disrupting this gut-brain endocrine axis contributes to hyperphagia underlying obesity. Further, GUCY2C is expressed by DA neurons in the SN, where it plays a role in memory and behavior. Our preliminary studies suggest that GUCY2C supports mitochondrial biogenesis protecting DA neurons in the SN from toxic insults. Thus, silencing GUCY2C amplifies DA neuron degeneration in the SN induced by MPTP, a mitochondrial toxin that selectively kills DA neurons. This DA neuron toxicity is associated with depletion of DA and its metabolites from the striatum, and induction of inflammation and reactive gliosis in the SN. Moreover, silencing GUCY2C in DA neurons depletes mitochondria, and their associated electron transport complexes, from the SN, characteristic of toxic insults in PD. These preliminary studies suggest a model in which the GUCY2C-signaling axis controls midbrain vulnerability to toxic insults by supporting mitochondrial biogenesis protecting DA neurons in the SN. Studies here explore two novel hypotheses. The Therapeutic Hypothesis suggests that toggling GUCY2C in the midbrain “OFF” (genetically), or “ON” (linaclotide stimulation) modulates the vulnerability of DA neurons to toxic degeneration. The Mechanistic Hypothesis suggests that GUCY2C protects the integrity of SN DA neurons through PGC1α- dependent mitochondrial biogenesis. These studies will reveal a therapeutic target (midbrain GUCY2C), a mechanism (mitochondrial biogenesis) that may be generalizable to the spectrum of toxic insults in the midbrain, and a specific therapeutic paradigm (linaclotide) to prevent midbrain DA neurodegeneration. The potential to translate these studies into new strategies to prevent and treat PD can best be appreciated by considering that the GUCY2C agonists linaclotide and plecanatide are FDA-approved to treat chronic constipation syndromes.

帕金森病 (PD) 是美国与年龄相关的神经退行性疾病的第二大常见原因。 PD，黑质 (SN) 中脑多巴胺 (DA) 神经元的线粒体功能障碍诱导氧化 压力和细胞死亡。反过来，这种神经变性会导致 DA 耗尽，这是运动神经元的基础 功能障碍和痴呆是这种疾病的特征。目前的疗法可提高 DA 水平以缓解运动症状 症状，但不能阻止神经退行性变、疾病进展或死亡。因此，有一个必不可少的 开发新的治疗策略来保护 DA 神经元免于变性以预防和治疗的需求未得到满足 治疗PD。鸟苷酸环化酶 C (GUCY2C) 是一种肠道受体，负责调节局部产生的激素 分泌，这是批准 GUCY2C 激动剂利那洛肽治疗便秘的基础。在肠道中，该受体 信号轴还通过转录辅激活因子 PGC1α 支持线粒体生物发生，其 破坏导致线粒体功能障碍，这是癌症病理生理学的核心；炎症性肠 疾病;和中毒性损伤。最近，GUCY2C 激素轴作为内分泌的传入肢出现。 控制大脑中两个离散回路的通路。下丘脑腹侧神经元中的 GUCY2C 前乳头核控制瘦素信号调节食欲。扰乱肠脑内分泌轴 导致肥胖引起的食欲过盛。此外，GUCY2C 由 SN 中的 DA 神经元表达，其中 它在记忆和行为中发挥作用。我们的初步研究表明 GUCY2C 支持线粒体 生物发生保护 SN 中的 DA 神经元免受毒性损伤。因此，沉默 GUCY2C 会放大 DA 神经元 MPTP（一种选择性杀死 DA 神经元的线粒体毒素）诱导的 SN 变性。这个 DA 神经元 毒性与纹状体中 DA 及其代谢物的消耗以及炎症的诱导有关 和 SN 中的反应性神经胶质增生。此外，沉默 DA 神经元中的 GUCY2C 会消耗线粒体，并且其 相关的电子传递复合物，来自 SN，是 PD 中毒性损伤的特征。这些初步的 研究提出了一个模型，其中 GUCY2C 信号轴通过以下方式控制中脑对毒性损伤的脆弱性： 支持线粒体生物发生，保护 SN 中的 DA 神经元。这里的研究探索了两部小说 假设。治疗假说表明，通过基因方式“关闭”中脑中的 GUCY2C， 或“ON”（利那洛肽刺激）调节 DA 神经元对毒性变性的脆弱性。这 机制假设表明 GUCY2C 通过 PGC1α-保护 SN DA 神经元的完整性 依赖线粒体生物发生。这些研究将揭示一个治疗靶点（中脑 GUCY2C）， 机制（线粒体生物发生）可推广到中脑毒性损伤的范围， 以及预防中脑 DA 神经变性的特定治疗范例（利那洛肽）。潜力 将这些研究转化为预防和治疗 PD 的新策略，最好考虑以下因素： GUCY2C 激动剂利那洛肽和普卡那肽已获得 FDA 批准用于治疗慢性便秘综合征。