Unfolded Protein Response in Alpha-synucleinopathies

α-突触核蛋白病中未折叠的蛋白质反应

• 批准号: 9203644
• 负责人: MICHAEL K LEE
• 金额: $ 33.33万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-15 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9203644
• 关键词: Aging; Alzheimer' s Disease; Attenuated; Brain; Cell Death; Cells; Cellular biology; Chronic; Development; Disease; Dopamine; Etiology; Event; Exhibits; Functional disorder; Future; Genetic; Human; In Vitro; Lead; Lewy Body Dementia; Link; Mind; Mitochondria; Modeling; Molecular; Molecular Abnormality; Molecular Biology; Multiple System Atrophy; Mus; Mutation; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Oligodendroglia; Onset of illness; Oxidative Stress; Parkinson Disease; Partner in relationship; Pathogenicity; Pathologic; Pathology; Pathway interactions; Pharmacological Treatment; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Property; Protein Dephosphorylation; Proteins; Quality Control; Reticulum; Rodent Model; Role; Specificity; Stress; Testing; Therapeutic Effect; Toxic effect; Transgenic Mice; Validation; alpha synuclein; alpha synuclein gene; arm; attenuation; base; biological adaptation to stress; effective therapy; endoplasmic reticulum stress; genetic approach; in vivo; mitochondrial dysfunction; mouse model; neuropathology; neurotoxicity; new therapeutic target; novel; novel therapeutics; protein aggregation; protein degradation; public health relevance; response; stressor; synucleinopathy; targeted treatment; therapeutic target; therapy development; transcription factor CHOP

DESCRIPTION (provided by applicant): Alpha-synuclein abnormalities are implicated in a number of neurodegenerative diseases; including Parkinson's disease (PD), Lewy Body Dementia (LBD), and Multiple Systems Atrophy (MSA). Because alpha-synuclein aggregates in neurons (PD, LBD) and/or oligodendrocytes (MSA) are prominent pathological features of these diseases, they are categorized as alpha-synucleinopathies. Collectively, alpha-synucleinopathies represent the second most common late-onset neurodegenerative disease, next to Alzheimer's disease (AD). While there are no effective therapies that can slow or stop the progression of neurodegeneration associated with alpha-synucleinopathies, availability of multiple transgenic mouse models of various alpha-synucleinopathies allows us to better understand the genesis of alpha-synuclein abnormalities in vivo and mechanisms of neurodegeneration in brain. These efforts will likely lead to identifying novel therapeutic targets for alpha-synucleinopathies. Presence of intracellular alpha-synuclein aggregates in alpha-synucleinopathy suggest that some aspect of protein degradation/quality control is dysfunctional in the diseases. Consistent with this view, we found that neurodegeneration in cellular and transgenic mouse models of neuronal alpha-synucleinopathy is associated with chronic Endoplasmic Plasmic Reticulum Stress (ERS) with abnormal Unfolded Protein Response (UPR). Our studies indicate that ERS is initiated by translocation and aggregation of alpha-synuclein within the ER. More important, pharmacological treatment with an anti-ERS compound, Salubrinal, significantly delays disease manifestation in rodent model of neuronal alpha-synucleinopathy. These results suggest that ERS response pathway, particularly modulation of phospho-eIF2alpha levels could represent a novel therapeutic target for PD and other alpha-synucleinopathies. However, because of compounds such as Salubrinal may have unknown off-target effects in vivo, a rigorous validation the phospho-eIF2alpha as therapeutic target at molecular levels are needed. Further, it is not clear if all alpha-synucleinopathies shar common neurodegenerative mechanisms. With these issues in mind, we propose following studies. First, we will study whether chronic ERS is a general feature of alpha-synucleinopathy by studying ERS in both neuronal and glial alpha-synucleinopathies (PD, LBD, MSA). Second, we will determine if aging related factors, such as oxidative stress/mitochondrial dysfunction, promotes ER accumulation of alpha-synuclein oligomers. Finally, we will determine whether the genetic alterations in components of the Perk/eIF2alpha arm of the ERS have predictable effects on alpha-synuclein dependent neurodegeneration. These studies will establish the value of ER stress pathway, particularly Perk/eIF2alpha components, as targets for development of novel therapies for PD.

描述（由申请人提供）：α-突触核蛋白异常与许多神经退行性疾病有关;包括帕金森病（PD）、路易体痴呆（LBD）和多系统萎缩（MSA）。因为神经元（PD、LBD）和/或少突胶质细胞（MSA）中的α-突触核蛋白聚集体是这些疾病的突出病理特征，所以它们被归类为α-突触核蛋白病。总的来说，α-突触核蛋白病代表仅次于阿尔茨海默病（AD）的第二种最常见的迟发性神经退行性疾病。虽然没有有效的疗法可以减缓或停止与α-突触核蛋白病相关的神经变性的进展，但多种α-突触核蛋白病的转基因小鼠模型的可用性使我们能够更好地了解体内α-突触核蛋白异常的起源和脑中神经变性的机制。这些努力将可能导致确定新的治疗靶点 α-突触核蛋白病α-突触核蛋白病中细胞内α-突触核蛋白聚集体的存在表明蛋白质降解/质量控制的某些方面在疾病中功能失调。与这一观点一致，我们发现神经元α-突触核蛋白病的细胞和转基因小鼠模型中的神经变性与慢性内质网应激（ERS）和异常未折叠蛋白反应（UPR）相关。我们的研究表明，ERS是启动的移位和聚集的α-突触核蛋白在ER。更重要的是，用抗ERS化合物Salubrinal的药理学治疗显著延迟神经元α-突触核蛋白病啮齿动物模型中的疾病表现。这些结果表明，ERS反应途径，特别是磷酸-eIF 2 α水平的调节可能代表PD和其他α-突触核蛋白病的新治疗靶点。然而，由于化合物如Salubrinal在体内可能具有未知的脱靶效应，因此需要在分子水平上严格验证磷酸-eIF 2 α作为治疗靶标。此外，尚不清楚是否所有α-突触核蛋白病都具有共同的神经退行性机制。考虑到这些问题，我们建议进行以下研究。首先，我们将通过研究神经元和神经胶质α-突触核蛋白病（PD，LBD，MSA）中的ERS来研究慢性ERS是否是α-突触核蛋白病的一般特征。其次，我们将确定是否老化相关因素，如氧化应激/线粒体功能障碍，促进ER积累的α-突触核蛋白寡聚体。最后，我们将确定ERS的Perk/eIF 2 α臂组分的遗传改变是否对α-突触核蛋白依赖性神经变性具有可预测的影响。这些研究将确立ER应激通路的价值，特别是Perk/eIF 2 α组分，作为PD新疗法开发的靶点。