BACKGROUND Multiple system atrophy (MSA) is a progressive, neurodegenerative disease characterized by parkinsonism, resistance to dopamine therapy, ataxia, autonomic dysfunction, and pathological accumulation of α-synuclein (α-syn) in oligodendrocytes. Neurosin (kallikrein-6) is a serine protease capable of cleaving α-syn in the CNS, and we have previously shown that lentiviral (LV) vector delivery of neurosin into the brain of a mouse model of dementia with Lewy body/ Parkinson's disease reduces the accumulation of α-syn and improves neuronal synaptic integrity. RESULTS In this study, we investigated the ability of a modified, systemically delivered neurosin to reduce the levels of α-syn in oligodendrocytes and reduce the cell-to-cell spread of α-syn to glial cells in a mouse model of MSA (MBP-α-syn). We engineered a viral vector that expresses a neurosin genetically modified for increased half-life (R80Q mutation) that also contains a brain-targeting sequence (apoB) for delivery into the CNS. Peripheral administration of the LV-neurosin-apoB to the MBP-α-syn tg model resulted in accumulation of neurosin-apoB in the CNS, reduced accumulation of α-syn in oligodendrocytes and astrocytes, improved myelin sheath formation in the corpus callosum and behavioral improvements. CONCLUSION Thus, the modified, brain-targeted neurosin may warrant further investigation as potential therapy for MSA.

中文翻译：

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在多系统萎缩的小鼠模型中，以大脑为目标的修饰神经毒素（激肽释放酶6）可以减少α-突触核蛋白的积累。

背景技术多系统萎缩症（MSA）是一种进行性神经退行性疾病，其特征为帕金森氏症，对多巴胺疗法的抵抗，共济失调，自主神经功能障碍以及少突胶质细胞中α-突触核蛋白（α-syn）的病理性蓄积。Neurosin（激肽释放酶-6）是一种能够在CNS中裂解α-syn的丝氨酸蛋白酶，我们以前已经证明慢病毒（LV）载体将Neurosin传递到患有路易体/帕金森氏病的痴呆症小鼠模型的大脑中α-syn的积累并改善神经元突触的完整性。结果在这项研究中，我们研究了修饰的，全身递送的神经球蛋白在MSA（MBP）小鼠模型中降低少突胶质细胞中α-syn的水平并减少α-syn在神经胶质细胞之间的扩散的能力。 -α-syn）。我们设计了一种病毒载体，该病毒载体表达经过基因修饰的神经素，可延长半衰期（R80Q突变），其中还包含一个脑靶向序列（apoB），可传递至CNS。向MBP-α-syntg模型外周施用LV-neurosin-apoB导致CNS中神经元-apoB的积累，少突胶质细胞和星形胶质细胞中α-syn的积累减少，improved体中髓鞘鞘的形成和行为改善改进。结论因此，经过修饰的，以脑为靶点的神经素可能需要进一步研究，作为MSA的潜在治疗方法。向MBP-α-syntg模型外周施用LV-neurosin-apoB导致CNS中神经元-apoB的积累，少突胶质细胞和星形胶质细胞中α-syn的积累减少，improved体髓鞘形成的改善和行为改进。结论因此，经过修饰的，以脑为靶点的神经素可能需要进一步研究，作为MSA的潜在治疗方法。向MBP-α-syntg模型外周施用LV-neurosin-apoB导致CNS中神经元-apoB的积累，少突胶质细胞和星形胶质细胞中α-syn的积累减少，improved体髓鞘形成的改善和行为改进。结论因此，经过修饰的，以脑为靶点的神经素可能需要进一步研究，作为MSA的潜在治疗方法。