Alterations in synaptic growth and lipid-raft organization in a fly MLIV model

果蝇 MLIV 模型中突触生长和脂筏组织的变化

基本信息

批准号：
8696544
负责人：
KARTIK VENKATACHALAM
金额：
$ 33.25万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8696544
关键词：
Address Affect Age Biochemical Biological Process Brain Brain imaging Cations Cell membrane Cells Childhood Cholesterol Clinical Trials Cognitive Corpus Callosum Data Defect Development Disease Disease Outcome Drosophila genus Drug usage Endocytosis Enzymes Esterification Esters Exhibits Functional disorder Ganglioside Sialidase Deficiency Disease Generations Genetic Goals Growth Hereditary Disease Homologous Gene JUN gene Larva Link Lysosomal Storage Diseases Lysosomes Malignant Neoplasms Membrane Membrane Microdomains Methodology Mitogen-Activated Protein Kinases Modeling Molecular Mutation Nature Nerve Degeneration Neurobiology Neurologic Neurological outcome Neuromuscular Junction Neuronal Dysfunction Neurons Patients Phenotype Phosphotransferases Process Proteins Publishing Resolution Signal Transduction Spielmeyer-Vogt Disease Synapses Testing Therapeutic Vesicle axon growth base cohort esterase fly in vivo insight late endosome lipoprotein cholesterol loss of function mutation neuropathology new technology novel novel strategies pleiotropism prevent public health relevance receptor binding signal processing tool

项目摘要

DESCRIPTION (provided by applicant): Many lysosomal storage diseases (LSDs) cause childhood-onset neurodegeneration leading to profound psychomotor retardation and ophthalmological abnormalities. In general, LSDs are notoriously difficult to treat because although these diseases are monogenic in origin, they typically affect a host of cellular signaling cascades and cell biological processes. The pleiotropy associated with LSDs prevents the development of suitable therapeutic strategies that simultaneously target the multiple disease outcomes. Moreover, it is becoming increasingly clear that LSDs are also characterized by neurodevelopmental abnormalities such as diminished axonal development in the cortex and corpus callosum. Unfortunately, the mechanistic basis for these neuronal defects associated with LSDs remain poorly understood. The overarching goal of this proposal is to address these conceptual gaps using a Drosophila model of an LSD called mucolipidosis type IV (MLIV) that arises from loss of function mutations in a lysosomal Ca2+ channel called TRPML1. We previously established that the fly TRPML1 homolog, TRPML, is a late-endosomal/amphisomal Ca2+ channel that drives the fusion of these vesicles with lysosomes. Here, we will leverage the genetic tractability of the Drosophila to address the critical mechanistic questions regarding the neuropathology of LSDs. In Aim 1, we will test the hypothesis that loss of TRPML results in alterations in the organization of cholesterol-enriched ordered membrane microdomains called lipid rafts. Because lipid rafts are critical for the functioning of a plethora of cellular signalig processes, alterations in the stability of these domains could provide a mechanistic explanation for the pleiotropy associated with lysosomal dysfunction. In Aim 2, we will test the hypothesis that TRPML promotes synaptic growth by activating developmental c-Jun Kinase (JNK) signaling in neurons. Interestingly, diminished JNK activation results in hypoplasia and agenesis of axonal tracts of the cortex and corpus callosum. Therefore, decreased JNK activation following lysosomal dysfunction signaling may be the molecular explanation for why LSDs are characterized by axonal growth defects. If successful, these studies should provide us with mechanistic insight into some of the common neurological outcomes associated with lysosomal dysfunction and also aid in the establishment of concepts for therapeutically targeting the neurological sequelae of LSDs.

描述（由申请人提供）：许多溶酶体贮积症（LSD）会导致儿童期发病的神经变性，导致严重的精神运动迟缓和眼科异常。一般来说，LSD 是出了名的难以治疗，因为尽管这些疾病起源于单基因，但它们通常会影响许多细胞信号传导级联和细胞生物过程。 LSD 的多效性阻碍了同时针对多种疾病结果的合适治疗策略的开发。此外，越来越清楚的是，LSD 还具有神经发育异常的特征，例如皮质和胼胝体轴突发育减弱。不幸的是，人们对这些与 LSD 相关的神经元缺陷的机制基础仍然知之甚少。该提案的首要目标是使用称为 IV 型粘脂沉积症 (MLIV) 的 LSD 果蝇模型来解决这些概念差距，这种 LSD 是由称为 TRPML1 的溶酶体 Ca2+ 通道功能缺失突变引起的。我们之前确定，果蝇 TRPML1 同源物 TRPML 是一种晚期内体/两性 Ca2+ 通道，可驱动这些囊泡与溶酶体的融合。在这里，我们将利用果蝇的遗传易处理性来解决有关 LSD 神经病理学的关键机制问题。在目标 1 中，我们将检验以下假设：TRPML 的缺失会导致富含胆固醇的有序膜微域（称为脂筏）的组织发生变化。由于脂筏对于大量细胞信号过程的功能至关重要，因此这些结构域稳定性的改变可以为与溶酶体功能障碍相关的多效性提供机制解释。在目标 2 中，我们将测试 TRPML 通过激活神经元中发育性 c-Jun 激酶 (JNK) 信号传导来促进突触生长的假设。有趣的是，JNK 激活减少会导致皮质和胼胝体轴突束发育不全和发育不全。因此，溶酶体功能障碍信号传导后 JNK 激活减少可能是 LSD 以轴突生长缺陷为特征的分子解释。如果成功，这些研究将为我们提供与溶酶体功能障碍相关的一些常见神经系统结果的机制见解，并有助于建立针对 LSD 神经系统后遗症的治疗概念。