Spastic paraplegia, neurodegeneration and autism: possible role for AT-1/SLC33A1?

痉挛性截瘫、神经退行性变和自闭症：AT-1/SLC33A1 的可能作用？

• 批准号: 9271256
• 负责人: Luigi Puglielli
• 金额: $ 33.1万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-20 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9271256
• 关键词: Acetyl Coenzyme A; Acetylation; Acetyltransferase; Affect; Animals; Area; Autistic Disorder; Autophagocytosis; Behavioral; Biochemical; Biochemistry; Biological; Biology; Biomedical Research; Cell Nucleus; Cell physiology; Cessation of life; Collaborations; Cytoplasm; Cytosol; Data; Databases; Defect; Development; Developmental Delay Disorders; Disease; Endoplasmic Reticulum; Event; Functional disorder; Generations; Genes; Grant; Human; Immune system; Impairment; In Vitro; Infection; Inflammatory Response; Intellectual functioning disability; Knock-in Mouse; Laboratories; Lysine; Magnetic Resonance; Malignant Neoplasms; Mass Spectrum Analysis; Membrane; Membrane Transport Proteins; Modeling; Molecular; Molecular Conformation; Mus; Mutation; Nerve Degeneration; Nervous system structure; Neuraxis; Neurons; Organelles; Pathologic; Pathology; Pathway interactions; Patients; Peripheral; Phenotype; Physiological; Physiology; Post-Translational Protein Processing; Proteins; Reaction; Regulation; Reporting; Research; Role; Signal Transduction; Spastic Paraplegia; Structure; Testing; Transgenic Mice; autism spectrum disorder; base; disease phenotype; human disease; in vivo; inhaled nitric oxide; meetings; motor deficit; mouse model; nervous system disorder; novel; novel therapeutic intervention; overexpression; polypeptide; premature; protein expression; protein transport; public health relevance; response; sensor

 DESCRIPTION (provided by applicant): Nε-lysine acetylation is an essential post-translational modification. It regulates activity, molecular stabilization and conformational assembly of targeted proteins. For more than forty years it was assumed that lysine acetylation could only occur in the cytosol and nucleus. However, in 2007, we reported the transient lysine acetylation of endoplasmic reticulum (ER) cargo proteins. Subsequent studies revealed that the ER has two acetyltransferases (ATase1 and ATase2) as well as a membrane transporter (AT-1/SCL33A1) that translocates acetyl-CoA, donor of the acetyl group for the reaction of acetylation, into the ER lumen. AT- 1/SCL33A1 is essential for the intraluminal acetylation of ER-resident and -transiting proteins. Changes in acetyl-CoA influx affect the acetylation status of the ER. Heterozygous mutations in AT-1/SCL33A1 have been identified in patients affected by a familial form of spastic paraplegia while homozygous mutations have been identified in patients affected by developmental delay of the nervous system and premature death. Finally, a duplication of AT-1/SCL33A1 has been reported in patients with autism spectrum disorder and intellectual disability. The general hypothesis of our research is that tight regulation of acetyl-CoA influx ino the ER lumen by AT-1 is essential for neuron biology. To test the above hypothesis we have generated mouse models of reduced (AT-1S113R/+) and increased (AT-1 Tg) acetyl-CoA influx into the ER. AT-1S113R/+ mice develop deficits of both the immune and nervous system. The defects of the immune system result in increased propensity to infections, aberrant inflammatory response, and increased propensity to malignancies. The defects of the nervous system result into severe motor deficits and degenerative features of the peripheral (PNS) and central (CNS) nervous system. AT-1 Tg mice display an autistic-like phenotype with behavioral deficits, impaired LTP and LTD, and increased neuronal branching. The data collected so far suggests that the ER-based acetylation machinery regulates the efficiency of protein trafficking along the secretory pathway and the induction of ERAD(II). Specific Aim 1 will test the hypothesis that the S113R (associated with spastic paraplegia) and A110P (associated with developmental delay) mutations affect the structure of AT-1 and block post-translational assembly of the transporter in the ER membrane. Specific Aim 2 will test the hypothesis that Atg9A acts as a "sensor" of acetyl-CoA levels in the ER lumen and regulates induction of ERAD(II)/autophagy down-stream of AT-1. Together, Aim 1 and Aim 2 will dissect the molecular basis of diseases associated with deficient ER acetylation. Specific Aim 3 will test the hypothesis that abnormally high influx of acetyl-CoA into the ER lumen in AT-1 Tg mice increases the efficiency of the secretory pathway beyond physiological requirements and causes broad changes on protein expression levels in the neuron. This Aim will dissect the molecular basis of the autism spectrum disorder and intellectual disability associated with the duplication of AT-1/SCL33A1.

 描述（由应用程序提供）：Nε-赖氨酸乙酰化是一种必不可少的翻译后修饰。它调节靶蛋白的活性，分子稳定和构象组装。四十多年来，假设仅在细胞质和核中才能发生赖氨酸乙酰化。但是，在2007年，我们报道了内质网（ER）货物蛋白的瞬时赖氨酸乙酰化。随后的研究表明，ER具有两个乙酰基转移酶（ATASE1和ATASE2）以及一个膜转运蛋白（AT-1/SCL33A1），这些乙酰转移蛋白转化乙酰基-COA，乙酰基-COA，乙酰基组的供体，用于乙酰反应的乙酰反应，乙酰乙酰基乙酰基乙烯基，乙酰反应。 AT-1/SCL33A1对于内部乙酰居民和传输蛋白是必不可少的。乙酰-COA影响的变化会影响ER的乙酰状态。在受痉挛性截瘫的家庭形式影响的患者中，已经发现了AT-1/SCL33A1中的杂合突变，而在神经系统延迟和过早死亡影响的患者中，已经确定了纯合突变。最后，已经报道了自闭症谱系障碍和智障患者的AT-1/SCL33A1的重复。我们研究的总体假设是，AT-1对乙酰辅酶A的严格调节对INO腔腔是神经元生物学至关重要的。为了检验上述假设，我们已经生成了减少（AT-1S113R/+）的小鼠模型，并增加了（AT-1 TG）乙酰-COA对ER的影响。 AT-1S113R/+小鼠开发了免疫系统和神经系统的定义。免疫系统的缺陷导致对感染的可靠性提高，异常炎症反应以及对恶性肿瘤的可靠性提高。神经系统的缺陷导致周围（PNS）和中央（CNS）神经系统的严重运动缺陷和退化特征。 AT-1 TG小鼠表现出具有行为缺陷，LTP和LTD受损的加速表型，并增加了神经元分支。迄今为止收集的数据表明，基于ER的乙酰化机制调节沿秘密途径和诱导ERAD（II）的蛋白质运输效率（II）。具体目标1将检验以下假设：S113R（与痉挛性截瘫有关）和A110p（与发育延迟）突变会影响ER膜中转运蛋白的AT-1和阻滞后翻译后组装的结构。具体目标2将检验以下假设：ATG9A充当ER管腔中乙酰-COA水平的“传感器”，并调节AT-1的ERAD（II）/自噬下游的诱导。共同，AIM 1和AIM 2将剖析与确定性ER乙酰化相关的疾病的分子基础。特定的目标3将检验以下假设：AT-1 TG小鼠中乙酰辅酶A对ER管腔的绝对高影响提高了秘密途径的效率，超出了物理要求，并导致神经元中蛋白质表达水平的广泛变化。该目标将剖析自闭症谱系障碍和智力障碍的分子基础与AT-1/SCL33A1的重复有关。