Hedgehog Signaling in the Brain Contributes to Alzheimer’s Disease in a Drosophila Model

大脑中的刺猬信号传导导致果蝇模型中的阿尔茨海默病

• 批准号: 10706662
• 负责人: Jianhang Jia
• 金额: $ 28.71万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10706662
• 关键词: Adult; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Biochemical; Brain; Cholesterol; Complement 4b; Complement component C4a; Critical Pathways; Defect; Disease model; Drosophila genus; Embryonic Development; Erinaceidae; G-Protein-Coupled Receptors; Genetic; Human; Insecta; Investigation; Knowledge; Longevity; Mammals; Modeling; Nerve Degeneration; Neurodegenerative Disorders; Pathway interactions; Pattern; Pattern Formation; Play; Process; Proliferating; Protein Family; Role; Signal Transduction; cancer type; cell growth; cholesterol biosynthesis; dopaminergic neuron; fly; hedgehog signal transduction; insight; novel; protective effect; smoothened signaling pathway; stem cells

Abstract: Hedgehog (Hh) signaling plays critical roles in pattern formation, embryonic development, and cell growth control; however, its function(s) in adulthood remain largely unknown although the mylfunction of Hh signaling causes several types of cancer. Hh signaling has also been shown to be involved in neurodegenerative disease and shown to regulate the proliferation of neuroal stem cells. It is unknown whether Hh signaling is involved in Alzheimer’s disease. Transduction of the Hh signal requires the G protein-coupled receptor (GPCR) family protein Smoothened (Smo) in both insects and mammals. Recent studies have demonstrated that cholesterol activates Smo through direct interaction and possibly covalent attachment. Whether and how cholesterol biosynthesis pathway regulates Smo are unclear. We recently discovered that Hh signaling activity maintains the viability of dopaminergic neurons in Drosophila adult brain. Inactivation of Hh signaling significantly decreased the lifespan of adult flies. In addition, we identified a non-canonical cholesterol biosynthesis pathway that critically regulates Smo. We have established a Alzhermer’s disease model by expressing human amyloid beta (Aβ) in adult flies. We hypothesize that the non-canonical cholesterol biosynthesis pathway plays a role in compromising the defects caused by Aβ expression. We will determine whether cholesterol biosynthesis protects dopaminergic neurons in the adult brain and modulates Drosophila lifespan (Aim 1). We will determine whether cholesterol biosynthesis provide a protective effect in Aβ-induced neurodegeneration of the Alzheimer’s disease model (Aim 2). Proposed studies use a combination of genetic and biochemical approaches to build on prior contributions and to transition to newly emergent avenues of inquiry. The knowledge gained from this study will provide novel insights into mechanisms of Hh signaling in the protection of neurodegeneration and Alzheimer’s disease.

摘要： Hhedgehog(HH)信号在模式形成、胚胎发育和细胞生长中起关键作用。 然而，它在成年期的功能(S)仍然很大程度上是未知的，尽管HH信号的主要功能 会导致几种癌症。HH信号也被证明与神经退行性疾病有关。 并被证明可以调节神经干细胞的增殖。目前尚不清楚HH信号是否参与了 阿尔茨海默氏症。HH信号的转导需要G蛋白偶联受体(GPCR)家族 昆虫和哺乳动物中的蛋白质光滑(Smo)。最近的研究表明，胆固醇 通过直接相互作用和可能的共价连接激活Smo。胆固醇是否以及如何 Smo的生物合成途径对Smo的调控尚不清楚。我们最近发现，HH信号活性维持在 果蝇成体脑多巴胺能神经元的活性。HH信号显著失活 降低了成年果蝇的寿命。此外，我们还发现了一种非典型的胆固醇生物合成途径。 这对Smo进行了严格的监管。我们通过表达人类淀粉样蛋白建立了阿尔茨海默病模型 成年果蝇体内的β(Aβ)。我们假设非规范的胆固醇生物合成途径在 妥协Aβ表达造成的缺陷。我们将确定胆固醇生物合成是否具有保护作用 成年大脑中的多巴胺能神经元和调节果蝇寿命(目标1)。我们将确定是否 胆固醇生物合成在β诱导的阿尔茨海默病神经变性中具有保护作用 模型(目标2)。拟议的研究使用遗传和生化方法的组合来建立在以前的基础上 并向新出现的调查途径过渡。从这项研究中获得的知识将 为HH信号在保护神经变性和阿尔茨海默氏症中的机制提供新的见解 疾病。