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

帕金森病(PD)是美国与年龄相关的神经变性的第二大常见原因。 PD，黑质(SN)中脑多巴胺(DA)神经元线粒体功能障碍诱导氧化 压力和细胞死亡。反过来，这种神经退行性变导致DA耗竭，这是运动的基础 功能障碍和痴呆症是这种疾病的特征。目前的治疗方法提高多巴胺水平以缓解运动 症状，但不能防止神经退化、疾病进展或死亡。因此，有一个必不可少的 尚未满足的需求是开发新的治疗策略，保护DA神经元免受退化，以防止和 治疗警局。鸟苷酸环化酶C(GUCY2C)是一种肠道受体，可与本地产生的荷尔蒙进行调节 分泌物，GUCY2C激动剂利纳氯肽被批准用于治疗便秘的基础。在肠道中，这种受体 信号轴还通过转录共激活因子pGc1α支持线粒体的生物发生，其 破坏产生癌症病理生理学中心的线粒体功能障碍；炎症性肠病 疾病；和中毒伤害。最近，GUCY2C激素轴作为内分泌的传入肢体出现 控制大脑中两个谨慎回路的通路。下丘脑腹侧区神经元中的GUCY2C 哺乳动物前核控制瘦素信号，调节食欲。打乱这个肠道-大脑内分泌轴 导致肥胖的吞噬过多。此外，GUCY2C由黑质中的DA神经元表达，其中 它在记忆和行为中扮演着一个角色。我们的初步研究表明GUCY2C支持线粒体 生物发生保护黑质中的DA神经元免受毒物伤害。因此，沉默GUCY2C可放大DA神经元 MPTP是一种线粒体毒素，选择性地杀死DA神经元，导致黑质变性。这个DA神经元 毒性与纹状体DA及其代谢物的耗竭和诱导炎症有关。 和SN中的反应性胶质细胞增多症。此外，沉默DA神经元中的GUCy2C会耗尽线粒体，而它们的 伴生的电子传递复合体，来自SN，是帕金森病中有毒侮辱的特征。这些初步的 研究表明，GUCY2C信号轴通过以下方式控制中脑对有毒侮辱的易感性 支持线粒体生物发生保护黑质DA神经元。这里的研究探索了两部小说 假设。治疗假说表明，触发中脑GUCY2C的功能(从基因上讲)是“关闭”的， 或“on”(利那氯肽刺激)调节DA神经元对毒性变性的易感性。这个 机制假说认为，GUCY2C通过Pgc1α-2保护黑质DA神经元的完整性。 依赖线粒体的生物发生。这些研究将揭示一种治疗靶点(中脑GUCY2C)，一种 机制(线粒体生物发生)，可以概括为中脑的有毒侮辱光谱， 和一种特定的治疗范例(利那氯肽)，以防止中脑DA神经退行性变。潜在的 将这些研究转化为预防和治疗帕金森病的新策略，最好是考虑到 GUCY2C激动剂利那克肽和普来卡那肽是FDA批准的用于治疗慢性便秘综合征的药物。

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.