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）是美国年龄相关性神经退行性疾病的第二大常见原因。 PD，黑质（SN）中中脑多巴胺（DA）神经元的线粒体功能障碍诱导氧化应激。 压力和细胞死亡。反过来，这种神经变性导致DA耗竭，这是运动的基础。 功能障碍和痴呆是这种疾病的标志。目前的治疗方法提高DA水平，以缓解运动 症状，但不能防止神经变性，疾病进展或死亡。因此，有必要 开发保护DA神经元免于变性的新的治疗策略，以预防和治疗DA神经元变性， 治疗PD。鸟苷酸环化酶C（GUCY 2C）是一种局部产生的激素的肠道受体， 分泌，批准GUCY 2C激动剂利那洛肽治疗便秘的基础。在肠道中，这种受体 信号轴还通过转录辅激活因子PGC 1 α及其受体支持线粒体生物发生 破坏产生线粒体功能障碍，对癌症的病理生理学至关重要; 疾病;和毒性损伤。最近，GUCY 2C激素轴作为内分泌的传入分支出现， 控制大脑中两个离散回路的通路。下丘脑腹侧神经元中的GUCY 2C 乳头体前核控制瘦素信号调节食欲。扰乱了肠脑内分泌轴 导致肥胖症的饮食过量此外，GUCY 2C由SN中的DA神经元表达，其中 它在记忆和行为中起着重要作用。我们的初步研究表明，GUCY 2C支持线粒体 生物发生保护SN中的DA神经元免受有毒损伤。因此，沉默GUCY 2C扩增DA神经元 MPTP是一种选择性杀死DA神经元的线粒体毒素。这个DA神经元 毒性与纹状体DA及其代谢产物的消耗和炎症诱导有关 以及SN中的反应性胶质增生。此外，沉默DA神经元中的GUCY 2C消耗线粒体，并且它们的神经元中的GUCY 2C的表达增加。 相关的电子传递复合物，从SN，在PD的毒性损伤的特点。这些初步 研究提出了一种模型，其中GUCY 2C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。本文研究了两种新的 假设治疗假说表明，在中脑“关闭”（遗传上）， 或“ON”（利那洛肽刺激）调节DA神经元对毒性变性的脆弱性。的 机制假说表明，GUCY 2C通过PGC 1 α- 依赖线粒体的生物合成这些研究将揭示一个治疗靶点（中脑GUCY 2C）， 机制（线粒体生物发生）可能可以推广到中脑的毒性损伤范围， 以及预防中脑DA神经变性的特定治疗范例（利那洛肽）。的潜力 将这些研究转化为预防和治疗PD的新策略，最好考虑到 GUCY 2C激动剂利那洛肽和普坎替林被FDA批准用于治疗慢性便秘综合征。