Regulation of the oligodendroglial accumulation of alpha-synuclein in Multiple System Atrophy

描述（由申请人提供）：突触核病是一组神经退行性疾病，在美国影响超过150万人。多系统萎缩（MSA）是一种以帕金森病和α-突触核蛋白（α-syn）的少突胶质积聚为特征的致命的、快速进展的突触核病。虽然在了解帕金森病的发病机制方面已经付出了相当大的努力，但对于MSA和α-syn在少突胶质细胞中积累导致神经退行性病理的机制尚不完全清楚。一种可能性是自噬失败可能导致α-syn从神经元向少突胶质细胞传播。我们最近发现，在MSA中，调节自噬的microRNA （miR-101, miR-30a, miR183, miR-96）受到影响。假设MSA中miRNA的失调可能会下调自噬，从而导致α-syn清除缺陷，从而从神经元向胶质细胞传播。目的是更好地了解自噬相关miRNA的改变参与MSA发病机制的机制，并评估调节miRNA作为MSA新治疗方法的潜在价值。为此，我们将采用综合策略，包括在室内独特的混合细胞培养、MSA转基因小鼠模型和来自多个部位的MSA患者的脑组织中进行研究。目标是：一。目的探讨在混合神经元-少突胶质细胞培养中，mirna的改变可能导致α-syn在胶质细胞中增殖的机制。两个。在转基因MSA模型中确定调节自噬的mirna是否能改善α-syn的病理和扩散。三。分析MSA中特异性mirna的变化与自噬靶点的区域关系。这些目标与NINDS 2014年PD“基础研究”建议一致。发现miRNA失调、自噬缺陷和α-syn扩散之间的联系，将有助于阐明MSA的发病机制，并为研究这些相互作用在其他神经退行性疾病中的作用打开大门。这些研究也可能导致MSA的新治疗策略的发展。

DESCRIPTION (provided by applicant): Synucleonopathies are a group of neurodegenerative disorders that affect over 1.5 million people in the US. Multiple system atrophy (MSA) is a fatal, rapidly progressive synucleonopathy characterized by parkinsonism and oligodendroglial accumulation of α-synuclein (α-syn). While considerable effort has been devoted at understanding the pathogenesis of Parkinson's Disease, less is known about MSA and the mechanisms through which α-syn accumulates in oligodendroglial cells, resulting in neurodegenerative pathology, is not completely clear. One possibility is that autophagy failure could lead to α-syn propagation from neurons to oligodendroglial cells. We recently found that in MSA microRNA (miR-101, miR-30a, miR183, miR-96) that regulate autophagy are affected. The HYPOTHESIS is that miRNA dysregulation in MSA might down-regulate autophagy, which in turn results in defective α-syn clearance with the consequent propagation from neurons to glia. The OBJECTIVES will be to better understand the mechanisms through which alterations in autophagy-related miRNAs are involved in the pathogenesis of MSA and to evaluate the potential value of modulating miRNA's as a novel therapeutical approach for MSA. For this purpose we will utilize a combined strategy including studies in unique mixed cell cultures in chambers, transgenic mouse models of MSA and brain tissues from MSA patients from multiple sites. The AIMS are: ONE. To investigate in mixed neuron- oligodendroglial cell cultures the mechanisms through which alterations in miRNAs might lead to α-syn propagation into glial cells. TWO. To determine in transgenic models of MSA if modulating miRNAs that regulate autophagy ameliorate the α-syn pathology and spreading. THREE. To analyze the regional relationship between alterations in specific miRNAs and autophagy targets in MSA. These goals are in agreement with the NINDS 2014 PD "Basic Research" recommendations. Finding a link between miRNA dysregulation, autophagy deficits, and α-syn spreading will shed light on pathogenesis of MSA, and will open the door for the study of these interactions in other neurodegenerative disorders. These studies could also lead to the development of novel therapeutical strategies for MSA.