Unfolded Protein Response in Alpha-synucleinopathies

描述(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，包括帕金森氏病(PD)、路易体痴呆(LBD)和多系统萎缩(MSA)。由于神经元(PD、LBD)和/或少突胶质细胞(MSA)中的α-突触核蛋白聚集是这些疾病的显著病理特征，它们被归类为α-突触核病。总体而言，阿尔法-突触核病是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。虽然目前还没有有效的治疗方法可以减缓或阻止与α-突触核病相关的神经退行性变的进展，但各种α-突触核病转基因小鼠模型的可用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内神经变性的机制。这些努力可能会导致确定新的治疗靶点。 治疗阿尔法-突触核病症。α-突触核病中细胞内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是功能失调的。与这一观点一致，我们发现神经元性α-突触核病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)有关。我们的研究表明，ERS是由α-突触核蛋白在内质网内的移位和聚集启动的。更重要的是，使用抗ERS化合物salubrine的药物治疗显著延迟了神经元性α-突触核病啮齿动物模型的疾病表现。这些结果表明，ERS反应途径，特别是对磷酸化eIF2α水平的调节，可能是帕金森病和其他α-突触核病的新的治疗靶点。然而，由于Salubrine等化合物在体内可能具有未知的非靶点效应，因此需要在分子水平上严格验证磷酸化eIF2α作为治疗靶点的有效性。此外，目前还不清楚是否所有的α-突触核病都有共同的神经退行性变机制。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细胞α-突触核病(PD、LBD、MSA)的ERS来研究慢性ERS是否是α-突触核病的一般特征。其次，我们将确定与衰老相关的因素，如氧化应激/线粒体功能障碍，是否促进α-突触核蛋白寡聚体的ER积累。最后，我们将确定ERS的PERK/eIF2α臂成分的基因改变是否对α-突触核蛋白依赖性神经退行性变具有可预测的影响。这些研究将确定内质网应激途径的价值，特别是Perk/eIF2α成分，作为开发帕金森病新疗法的靶点。

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.