Sphingolipid Rheostat in Neurodegeneration

神经退行性变中的鞘脂变阻器

• 批准号: 8287557
• 负责人: Lihong Zhao
• 金额: $ 26.96万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8287557
• 关键词: Acyl Coenzyme A; Address; Adult; Affect; Agonist; Alzheimer' s Disease; Anabolism; Brain; Cell Culture Techniques; Cell Death; Cell membrane; Cells; Cellular Membrane; Ceramides; Cerebellar Ataxia; Cessation of life; Complex; Defect; Dementia; Dihydrosphingosine; Disease; Employee Strikes; Endocytosis; Equilibrium; Event; Family member; Genes; HIV; Health; Hippocampus (Brain); Homeostasis; Human; Lead; Ligands; Light; Lipids; Lysosomal Storage Diseases; Mediating; Membrane; Membrane Proteins; Methods; Modeling; Mus; Mutant Strains Mice; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Organelles; Parkinson Disease; Parkinson' s Dementia; Parkinsonian Disorders; Patients; Phenotype; Play; Proteins; Purkinje Cells; Research; Role; Signal Pathway; Signal Transduction; Sphingolipids; Sphingosine-1-Phosphate Receptor; Testing; Transgenic Organisms; Vertebral column; acyl group; base; dihydroceramide desaturase; dihydrosphingosine 1-phosphate; early onset; in vivo; inorganic phosphate; lipid metabolism; mouse model; mutant; neurogenesis; neuronal survival; overexpression; pre-clinical; receptor; response; serine palmitoyltransferase; sphingosine 1-phosphate; synuclein

DESCRIPTION (provided by applicant): Sphingolipid rheostat changes have been implicated in many neurodegenerative diseases, such as Alzheimer's disease, HIV-induced dementia and Parkinson's disease. These changes could be pathogenic events or homeostatic responses, but the underlying mechanisms are not clear. To further explore the roles of sphingolipids in neurodegeneration, I will take advantage of a mouse CerS1 (ceramide synthase 1) mutant, which displays early-onset Purkinje cell degeneration and adult-onset widespread accumulation of protein inclusions in neurons. Steady state levels of ceramide/sphingolipid, especially C18 ceramide/sphingolipid, are decreased in the mutant brain, whereas a striking increase in signaling-potent sphingoid bases and their phosphorylated metabolites, especially dihydrosphingosine (dhS) and dhS-1-phosphate (dhS1P), has been observed. The reduction of ceramide and complex sphingolipids may result in deficiency in membrane protein targeting which could lead to protein inclusions, and/or membrane organelle defects. On the other hand, drastic increase of sphingoid bases might interfere with normal sphingolipid-mediated signaling. Because very few Purkinje cells die with visible protein inclusions, this early pathological event is likely to be caused by changes in signaling function. In contrast, the late event, protein inclusion formation, may be due to impaired structural functions of sphingolipids. To find out whether the drastic increase of sphingoid bases impairs neuronal functions and causes neurodegeneration of Purkinje cells, and whether reduction of total ceramide or C18 ceramide contributes to Purkinje cell death and/or accumulation of protein inclusions in other neurons, I will: 1) Identify the preclinical intracellular changes that are potentially regulated by sphingoid lipids, particularly sphingoid bases. The initial study will focus on sphingosine-1-phosphate (S1P) signaling via its receptor S1PR1 (S1P1). Because dhS1P is also an agonist for S1P receptors, I propose that excessive dhS1P interferes with S1P1 signaling. 2) Test whether modulating sphingolipid profile in vivo will modify the CerS1 mutant phenotype. Modulation of sphingolipid profile will be accomplished by two methods, decreasing serine palmitoyltransferase (SPT) activity by using Sptlc1 heterozygosity or increasing ceramide synthesis by transgenic overexpression of CerS6. The result of decreasing SPT activity in CerS1 mutant background will determine if the cause of the pathological event in question is due to increased sphingoid bases or decreased ceramide level. The result of CerS6 overexpression will confirm the conclusion and further determine whether reduction of total ceramide or C18 ceramide species is the cause.

描述（由申请人提供）：许多神经退行性疾病，例如阿尔茨海默氏病，HIV引起的痴呆症和帕金森氏病。这些变化可能是致病事件或稳态反应，但基本机制尚不清楚。为了进一步探索鞘脂在神经退行性中的作用，我将利用小鼠CERS1（神经酰胺合酶1）突变体，该突变体显示早期发作的Purkinje细胞变性，成人蛋白质包含蛋白在神经元中的广泛积累。神经酰胺/鞘脂的稳态水平，尤其是C18神经酰胺/鞘脂，在突变大脑中降低，而信号功能的鞘脂碱及其磷酸化的代谢物的显着增加，尤其是二氢磷酸盐（DHS）和DHS-1-1-磷酸盐（DHS-1-磷酸盐）（DHS1P），已经观察到。神经酰胺和复杂的鞘脂的还原可能导致膜蛋白靶向缺乏，这可能导致蛋白质内含物和/或膜细胞器缺陷。另一方面，鞘脂碱的急剧增加可能会干扰正常的鞘脂介导的信号传导。由于很少有浦肯野细胞死于可见蛋白夹杂物，因此这一早期病理事件可能是由信号传导功能变化引起的。相反，蛋白质纳入形成的后期事件可能是由于鞘脂的结构功能受损所致。找出鞘脂碱的急剧增加是否会损害神经元的功能并引起呼普kinje细胞的神经退行性，以及是否减少了神经酰胺或C18神经酰胺有助于Purkinje细胞死亡和/或其他神经元中蛋白质夹杂物的积累，尤其是确定预先细胞内的蜂窝状碱基。最初的研究将通过其受体S1PR1（S1P1）来关注鞘氨醇-1-磷酸（S1P）信号。由于DHS1P也是S1P受体的激动剂，因此我提出过多的DHS1P会干扰S1P1信号。 2）测试体内调节鞘脂谱是否会改变CERS1突变体表型。鞘脂谱的调节将通过两种方法来完成，通过使用SPTLC1杂合性或通过CERS6的转基因过表达来减少丝氨酸棕榈酰转移酶（SPT）活性。 CERS1突变体背景中SPT活性降低的结果将确定所讨论的病理事件的原因是由于鞘氨素碱基增加还是神经酰胺水平降低。 CERS6过表达的结果将确认结论，并进一步确定降低总神经酰胺或C18神经酰胺物种是原因。