Spencer Brian, Valera Elvira, Rockenstein Edward, Trejo-Morales Margarita, Adame Anthony, Masliah Eliezer
Department of Neurosciences, University of California, San Diego, La Jolla, CA, 92093, USA.
Department of Pathology, University of California, San Diego, La Jolla, CA, 92093, USA.
Mol Neurodegener. 2015 Sep 23;10:48. doi: 10.1186/s13024-015-0043-6.
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.
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.
Thus, the modified, brain-targeted neurosin may warrant further investigation as potential therapy for MSA.
多系统萎缩（MSA）是一种进行性神经退行性疾病，其特征为帕金森综合征、对多巴胺治疗耐药、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。神经丝氨酸蛋白酶（激肽释放酶-6）是一种能够在中枢神经系统中切割α-syn的丝氨酸蛋白酶，我们之前已经表明，将神经丝氨酸蛋白酶通过慢病毒（LV）载体导入路易体痴呆/帕金森病小鼠模型的大脑中，可以减少α-syn的蓄积并改善神经元突触完整性。
在本研究中，我们研究了一种经过修饰的、经全身给药的神经丝氨酸蛋白酶在多系统萎缩小鼠模型（MBP-α-syn）中降低少突胶质细胞中α-syn水平以及减少α-syn在细胞间向神经胶质细胞传播的能力。我们构建了一种病毒载体，该载体表达一种经过基因修饰以延长半衰期（R80Q突变）的神经丝氨酸蛋白酶，其还包含一个用于递送至中枢神经系统的脑靶向序列（载脂蛋白B）。将LV-神经丝氨酸蛋白酶-载脂蛋白B外周给予MBP-α-syn转基因模型，导致神经丝氨酸蛋白酶-载脂蛋白B在中枢神经系统中蓄积，减少了少突胶质细胞和星形胶质细胞中α-syn的蓄积，改善了胼胝体中的髓鞘形成并改善了行为。
因此，这种经过修饰的、脑靶向的神经丝氨酸蛋白酶作为多系统萎缩的潜在治疗方法可能值得进一步研究。
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