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）是一种不屈不挠的神经退行性疾病，病因不确定， 病理生理学。 MSA是一种独特的蛋白质病，其中α-突触核蛋白优先积累 少突endroglia而不是神经元。累积的α-核蛋白，称为神经胶质细胞包含 （GCI）被认为会引起少突胶质细胞功能的变化，例如神经营养的支持降低和 脱髓鞘，导致神经变性。我们已经开发了新颖的大鼠和非人类灵长类动物（NHP） 通过使用一种新型的胶质胶质细胞 - 营养性表达寡胶质细胞中的α-核蛋白模型 腺相关病毒（AAV）载体，Olig001。组织学分析表明寡聚01-的广泛表达 在整个纹状体中连接的α-突触核蛋白在大鼠大脑中的call体和call体，> 90％局部固定在 在神经元或星形胶质细胞中几乎没有表达的寡头。该模型还显示脱髓鞘 call体和纹状体的白质区类似于患者大脑中观察到的。分析 来自模型动物的GCIS显示，它们在Tyr39和Ser129上包含疾病特异性的磷酸化 与在帕金森氏病（PD）患者神经元中看到的α-突触核蛋白的修饰相同。 在MSA患者大脑中还发现了对MSA模型大脑中这些修饰的意外观察 （请参阅创新）进一步验证了该大鼠模型对MSA疾病机制研究的适用性。 虽然MSA和PD都是突触核苷，但长期以来一直认为这些病理的起源 两种疾病是不同的。观察MSA中疾病特异性化学修饰的观察 PD中观察到的内容表明这些不同的疾病之间的机理联系更紧密。尤其， 由于亚伯森酪氨酸激酶C-ABL的激活是PD中的关键疾病发射事件 Tyr39的磷酸化，C-ABL在MSA中可能起着相似的作用，并且化学抑制C- 在MSA中，ABL可能正在调整疾病。这表明MSA的治疗可能会受益于口服 正如我们为帕金森氏病所表明的那样，生物利用的，脑培养基C-ABL激酶抑制剂。使用此 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 在PD中发现的激活，为疾病修饰治疗铺平了道路。