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

 描述(申请人提供)：共核疾病是一组神经退行性疾病，在美国有超过150万人受到影响。多系统萎缩是一种以帕金森氏症和α-突触核蛋白少突胶质细胞聚集(α-SYN)为特征的致命性、进展性突触核病。虽然人们对帕金森氏病的发病机制进行了大量的研究，但对MSA以及α-SYN在少突胶质细胞中积聚从而导致神经退行性病变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从神经元传播到少突胶质细胞。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。假说是MSA中的miRNA失调可能下调自噬，进而导致α-SYN清除缺陷，进而从神经元传播到神经胶质细胞。目的是更好地了解自噬相关miRNAs改变在MSA发病机制中的作用机制，并评价调节miRNA作为治疗MSA的一种新方法的潜在价值。为此，我们将利用一种组合策略，包括在室内进行独特的混合细胞培养、MSA转基因小鼠模型和来自多个地点的MSA患者的脑组织的研究。目标是：一.目的：探讨在混合培养的神经元和少突胶质细胞中，miRNAs的改变可能导致α-SYN向神经胶质细胞扩散的机制。二。在msA的转基因模型中，确定调节自噬的miRNA是否能改善α-SYN的病理和传播。三。分析MSA中特定miRNAs的改变与自噬靶点之间的区域关系。这些目标与NINDS 2014 PD“基础研究”建议是一致的。发现miRNA失调、自噬缺陷和α-SYN传播之间的联系将有助于阐明MSA的发病机制，并将为研究其他神经退行性疾病中的这些相互作用打开大门。这些研究还可能导致开发新的治疗MSA的策略。

 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.