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

摘要： Hedgehog（Hh）信号在模式形成、胚胎发育和细胞生长中起着关键作用 然而，尽管Hh信号转导的mylfunction在成年期仍然是未知的， 会导致几种癌症Hh信号也被证明参与神经退行性疾病 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 老年痴呆症Hh信号的转导需要G蛋白偶联受体（GPCR）家族 蛋白Smoothened（Smo）在昆虫和哺乳动物中的作用。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 生物合成途径调控Smo的机制尚不清楚。我们最近发现，Hh信号活动维持着 果蝇成年脑内多巴胺能神经元的活力。Hh信号转导的失活显著 减少了成年苍蝇的寿命。此外，我们还发现了一个非经典的胆固醇生物合成途径， 严格控制着Smo。我们通过表达人淀粉样蛋白， β-淀粉样蛋白（Aβ）。我们假设非经典的胆固醇生物合成途径在 从而削弱由Aβ表达引起的缺陷。我们将确定胆固醇生物合成是否能保护 多巴胺能神经元在成年人的大脑和调节果蝇寿命（目的1）。我们将决定 胆固醇生物合成在Aβ诱导的阿尔茨海默病神经退行性变中提供保护作用 模型（目标2）。拟议的研究使用遗传和生物化学方法的组合，以建立在先前的基础上， 贡献和过渡到新出现的调查途径。从这项研究中获得的知识将 为Hh信号转导机制在神经变性和阿尔茨海默病保护中提供了新的见解 疾病

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.