Roles of SN27 in regulating glutamate receptors during neurodegeneration

SN27 在神经退行性变过程中调节谷氨酸受体的作用

• 批准号: 9027787
• 负责人: Huaxi Xu
• 金额: $ 39.98万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-15 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9027787
• 关键词: Affect; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein Precursor; Anatomy; Behavior; Binding; Brain; CCAAT-Enhancer-Binding Proteins; Cell membrane; Chromosomes; Chromosomes, Human, Pair 21; Cognitive deficits; Defect; Disease; Down Syndrome; Endocytosis; Exhibits; Family; Functional disorder; Gene Dosage; Generations; Genes; Glutamate Receptor; Glutamates; Health; Hippocampus (Brain); Impairment; Intervention; Knockout Mice; Learning; Link; Measures; Mediating; Memory; Memory impairment; MicroRNAs; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurotransmitters; Pathogenesis; Pathology; Pathway interactions; Patients; Phenotype; Play; Postsynaptic Membrane; Presynaptic Terminals; Production; Proteins; Recycling; Regulation; Role; Signal Transduction; Sorting - Cell Movement; Staging; Synapses; Synaptic plasticity; System; Tg2576; Transgenic Mice; Viral; Virus; amyloid precursor protein processing; member; mouse Ts65Dn; mouse model; neuron loss; neuropathology; neurotoxicity; nexin; novel; overexpression; postsynaptic; promoter; receptor; secretase; synaptic function; trafficking; transcription factor

DESCRIPTION (provided by applicant): Dysregulation of glutamate receptors (GluRs) has been observed in various neurodegerative diseases such as Alzheimer's disease (AD) and Down Syndrome (DS). However, the underlying mechanisms responsible for the changes in GluRs and the contribution of GluR dysregulation to neurodegeneration have remained largely elusive. In our preliminary studies, we found that the Sorting Nexin 27 (SNX27) protein can interact with GluRs and govern their trafficking to the plasma membrane for recycling. SNX27 is abundantly expressed in the brain and SNX27 homozygous knockout (KO) mice exhibit severe neuropathologies resembling those found in AD and DS patients. SNX27 heterozygous KO mice have memory deficits and their neurons have reduced GluR levels and synaptic dysfunction. DS is caused by an extra copy of chromosome 21 which results in over- dosage of the genes on this chromosome. We found that in DS patient brains, a microRNA gene on chromosome 21, miR-155, which negatively regulates the transcription factor C/EBP¿, was upregulated, accompanied by a concomitant reduction of C/EBP¿ and SNX27. We also show that C/EBP¿ positively regulates SNX27 expression. These results reveal a miR-155/C/EBP¿/SNX27 pathway that leads to GluR dysregulation and synaptic dysfunction in DS. Since late stage DS patients develop AD-like pathologies and cognitive deficits, we studied the effect of SNX27 on the generation of ¿-amyloid (A¿), which is the primary culprit in AD pathogenesis and is derived from ¿-amyloid precursor protein through sequential cleavages by ¿- and ¿-secretases. We found that overexpression of SNX27 reduces A¿ production and the level and activity of ¿-secretase as well. Therefore, we hypothesize that SNX27 plays an important role in regulating GluRs and thus synaptic function, and that SNX27 deficiency may contribute to neurodegeneration in DS and AD. In this proposal, we will further ascertain the participation of SNX27 in DS by: (1) corroborating the regulation of GluRs by SNX27 and its modulators (miR155 and C/EBP¿) in primary neurons~ (2) using virus systems to modulate miR155, C/EBP¿, and SNX27 levels in SNX27 deficient mice and Ts65Dn mice, and study whether the impaired phenotypes in these mice can be ameliorated~ and (3) generating brain-specific SNX27 transgenic (Tg) mice and crossing them with Ts65Dn mice to study any amelioration of pathology through SNX27 overexpression. Moreover, we will explore the role of SNX27 in AD. We will: (1) modulate the levels of SNX27 and determine whether and how ¿-secretase level/trafficking/activity and APP processing/A¿ generation are affected~ (2) study whether SNX27 is affected by and involved in A¿-mediated neurotoxicity and examine any changes in SNX27 in AD brains~ and (3) cross SNX27 Tg mice with Tg2576 AD mice and attempt to rescue impaired phenotypes in AD mice. These results will elucidate the role of SNX27 in regulating GluRs and synaptic functions in DS and AD, providing novel molecular mechanisms for disease pathogenesis/pathology.

描述（由适用提供）：在各种神经化学疾病（例如阿尔茨海默氏病）（AD）和唐氏综合症（DS）中观察到谷氨酸受体（GLURS）的失调（glurs）。但是，负责gl毛变化的基本机制以及Glur失调对神经退行性的贡献仍然很大程度上仍然是弹性的。在我们的初步研究中，我们发现排序Nexin 27（SNX27）蛋白可以与胶水相互作用，并控制其运输到质膜以进行回收。 SNX27基本上是在大脑中表达的，而SNX27纯合敲除（KO）小鼠暴露了与AD和DS患者中发现的相似的严重神经病理学。 SNX27杂合KO小鼠的记忆定义，其神经元降低了GLUR水平和突触功能障碍。 DS是由21号染色体的额外副本引起的，该副本导致该染色体上的基因过度吞噬。我们发现，在DS患者大脑中，MiR-155染色体上的microRNA基因对转录因子C/EBP？进行负调节，通过随之而来的C/EBP降低和SNX27进行了更新。我们还表明C/EBP阳性对SNX27表达式进行了积极调节。这些结果揭示了miR-155/c/ebp¿/snx27途径，导致DS中的GLUR失调和突触功能障碍。由于晚期DS患者会出现类似AD的病理和认知定义，因此我们研究了SNX27对 - 淀粉样淀粉样蛋白（a。）的影响，这是AD发病机理中的主要罪魁祸首，并源自 - 淀粉样蛋白的前体蛋白质，通过顺序裂解通过 - 淀粉样蛋白通过 - 和 - 和secretasess。我们发现SNX27的过表达降低了A的产生以及分泌酶的水平和活性。因此，我们假设SNX27在调节胶水和突触功能中起重要作用，而SNX27缺乏症可能有助于DS和AD中的神经变性。在这项建议中，我们将进一步确定SNX27在DS中的参与：（1）通过使用病毒系统来证实SNX27及其调节剂（MiR155和C/EBP？）在原发性神经元中对gl骨的调节，并使用病毒系统使用病毒系统来调节MiR155，C/EBP？以及SNX27水平以及SNX27的影响，以及SNX27频率的影响。这些小鼠的表型可以改善〜，（3）产生脑特异性SNX27转基因（TG）小鼠，并用TS65DN小鼠跨越它们，以研究通过SNX27过表达对病理的任何改善。此外，我们将探讨SNX27在AD中的作用。我们将：（1）调节SNX27的水平，并确定是否以及如何以及如何以及如何影响〜（2）研究是否受AS介导的神经毒性的影响并涉及SNX27是否受到AD和（3）cross SNX27中的任何变化的影响，并参与了SNX27的任何变化，并进行了（3）Cross Snx27 TG27 tg27 tg27 AD小鼠的表型受损。这些结果将阐明SNX27在DS和AD中的调节胶和突触功能中的作用，从而为疾病发病机理/病理提供了新颖的分子机制。