Kinase activation in multiple system atrophy

多系统萎缩中的激酶激活

• 批准号: 10252219
• 负责人: Milton H. Werner
• 金额: $ 38.59万
• 依托单位: INHIBIKASE THERAPEUTICS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-23 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10252219
• 关键词: ABL1 gene; Animal Model; Area; Astrocytes; Autonomic nervous system; Autonomic nervous system disorders; Autopsy; Bioavailable; Biochemical; Biochemistry; Brain; Brain Diseases; Cells; Cerebellar Ataxia; Cessation of life; Chemicals; Clinical; Clinical Trials; Corpus Callosum; Corpus striatum structure; Cytoplasmic Inclusion; Degenerative Disorder; Demyelinations; Dependence; Development; Diagnosis; Disease; Disease Progression; Disease model; Dysautonomias; Etiology; Event; Failure; Functional disorder; Future; Gastrointestinal tract structure; Histologic; Lead; Lewy Bodies; Life Expectancy; Link; Measures; Modeling; Modification; Multiple System Atrophy; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Oligodendroglia; Oral; Parkinson Disease; Parkinsonian Disorders; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Phenotype; Phosphorylation; Phosphotransferases; Play; Preparation; Process; Progressive Disease; Protein Tyrosine Kinase; Proteins; Proto-Oncogene Proteins c-abl; Published Comment; Rare Diseases; Rattus; Recovery of Function; Reproduction; Rodent Model; Role; Sampling; Serine; Structure; Study models; Substantia nigra structure; Testing; Therapeutic; Toxic effect; Work; adeno-associated viral vector; alpha synuclein; behavior measurement; behavioral phenotyping; brain dysfunction; cerebral atrophy; disability; disease disparity; disease mechanisms study; dopaminergic neuron; druggable target; human disease; inhibitor/antagonist; innovation; kinase inhibitor; mutant; nonhuman primate; novel; putamen; response; synucleinopathy; white matter

Multiple system atrophy (MSA) is an unrelenting neurodegenerative disorder with an uncertain etiology and pathophysiology. MSA is a unique proteinopathy in which alpha-synuclein accumulates preferentially in oligodendroglia rather than neurons. Accumulated alpha-synuclein, known as a glial cytoplasmic inclusion (GCI), is thought to elicit changes in oligodendrocyte function, such as reduced neurotrophic support and demyelination, leading to neurodegeneration. We have developed novel rat and nonhuman primate (NHP) models of MSA by expressing alpha-synuclein in oligodendroglia using a novel glialoligodendrocyte-trophic adeno-associated virus (AAV) vector, Olig001. Histological analysis showed widespread expression of Oligo01- linked alpha-synuclein throughout the striatum and corpus callosum in rat brain with >90% localized to oligodendroglia and little to no expression in neurons or astrocytes. The model also displays demyelination in the white matter tracts of the corpus callosum and striatum, similar to what is observed in patient brain. Analysis of GCIs from the model animals revealed that they contain disease-specific phosphorylations at Tyr39 and Ser129 that are identical to the modifications of alpha-synuclein seen in neurons of Parkinson's Disease (PD) patients. The unexpected observation of these modifications in MSA model brain were also found in MSA patient brain (see Innovation) further validated the suitability of this rat model for the study of disease mechanism in MSA. While both MSA and PD are synucleinopathies, it has long been thought that the origin of pathology for these two diseases were distinct. The observation of disease-specific chemical modifications in MSA that are identical to what is observed in PD suggests a closer mechanistic linkage between these disparate diseases. In particular, since activation of the Abelson tyrosine kinase c-Abl is a key disease-initiating event in PD that results in phosphorylation at Tyr39, it is possible that c-Abl plays a similar role in MSA and that chemical inhibition of c- Abl could be disease-modifying in MSA. This suggests that treatment for MSA may be benefited by an orally bioavailable, brain-penetrant c-Abl kinase inhibitor, just as we've shown for Parkinson's Disease. Using this newly defined model of MSA, we propose to determine whether MSA has the same critical dependency on c-Abl activation that has been found in PD, paving the way for disease modifying therapy.

多系统萎缩 (MSA) 是一种持续性的神经退行性疾病，其病因尚不清楚，并且 病理生理学。 MSA 是一种独特的蛋白质病，其中 α-突触核蛋白优先在 少突胶质细胞而不是神经元。积累的α-突触核蛋白，称为神经胶质细胞质包涵体 (GCI)，被认为会引起少突胶质细胞功能的变化，例如神经营养支持的减少和 脱髓鞘，导致神经退行性变。我们开发了新型大鼠和非人类灵长类动物 (NHP) 使用新型胶质少突胶质细胞营养蛋白在少突胶质细胞中表达α-突触核蛋白来建立 MSA 模型 腺相关病毒（AAV）载体，Olig001。组织学分析显示 Oligo01- 广泛表达 在大鼠大脑的纹状体和胼胝体中连接 α-突触核蛋白，其中 >90% 定位于 少突胶质细胞，在神经元或星形胶质细胞中几乎没有表达。该模型还显示脱髓鞘 胼胝体和纹状体的白质束，类似于在患者大脑中观察到的情况。分析 来自模型动物的 GCI 显示，它们在 Tyr39 和 Ser129 处含有疾病特异性磷酸化 这与帕金森病 (PD) 患者神经元中观察到的 α-突触核蛋白的修饰相同。 在 MSA 模型大脑中意外观察到的这些修饰也在 MSA 患者大脑中被发现 （见创新）进一步验证了该大鼠模型对于MSA疾病机制研究的适用性。 虽然 MSA 和 PD 都是突触核蛋白病，但长期以来人们一直认为这些疾病的病理学起源 两种疾病是截然不同的。 MSA 中相同疾病特异性化学修饰的观察 PD 中观察到的结果表明这些不同疾病之间存在更密切的机制联系。尤其， 因为 Abelson 酪氨酸激酶 c-Abl 的激活是 PD 的关键疾病引发事件，可导致 Tyr39 磷酸化，c-Abl 可能在 MSA 中发挥类似的作用，并且 c-Abl 的化学抑制 Abl 可以缓解 MSA 的疾病。这表明口服药物可能有益于 MSA 的治疗。 生物可利用的、脑渗透性 c-Abl 激酶抑制剂，正如我们针对帕金森病所展示的那样。使用这个 新定义的 MSA 模型，我们建议确定 MSA 是否对 c-Abl 具有相同的关键依赖性 PD 中发现的激活，为疾病修饰治疗铺平了道路。