摘要
Background: Multiple system atrophy (MSA) is a progressive, neurodegenerative disease characterized by parkinsonism, resistance to dopamine therapy, ataxia, autonomic dysfunction, and pathological accumulation of alpha-synuclein (alpha-syn) in oligodendrocytes. Neurosin (kallikrein-6) is a serine protease capable of cleaving alpha-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 alpha-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 alpha-syn in oligodendrocytes and reduce the cell-to-cell spread of alpha-syn to glial cells in a mouse model of MSA (MBP-alpha-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-alpha-syn tg model resulted in accumulation of neurosin-apoB in the CNS, reduced accumulation of alpha-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.
- 出版日期2015-9-23