Abstract
BackgroundMultiple 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.ResultsIn 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.ConclusionThus, the modified, brain-targeted neurosin may warrant further investigation as potential therapy for MSA.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-015-0043-6) contains supplementary material, which is available to authorized users.
Highlights
The synucleinopathies are a heterogeneous group of neurodegenerative disorders that affect 5 million people worldwide and includes Parkinson’s disease (PD), dementia with Lewy bodies (DLB), neurodegeneration with brain iron accumulation, pure autonomic failure (PAF) and multiple system atrophy (MSA) (Reviewed in [1])
Since we have previously shown that stereotaxic injection of LV-neurosin into the hippocampus reduced the local accumulation of neuronal α-syn in a mouse model of DLB [25], for this study we sought to determine if gene therapy with this vector would reduce the neurodegenerative process in a mouse model of Multiple system atrophy (MSA) [27, 28]
Modifications to neurosin increase its stability without decreasing its ability to degrade α-syn We have previously shown that neurosin, when expressed from a lentiviral vector is able to degrade α-syn and promote the survival of neuronal cells in culture when challenged with exogenous α-syn [25]. This vector was delivered by direct stereotaxic injection to an α-syn tg mouse model of DLB/PD
Summary
The synucleinopathies are a heterogeneous group of neurodegenerative disorders that affect 5 million people worldwide and includes Parkinson’s disease (PD), dementia with Lewy bodies (DLB), neurodegeneration with brain iron accumulation, pure autonomic failure (PAF) and multiple system atrophy (MSA) (Reviewed in [1]). Multiple system atrophy is a rapidly progressive, neurological condition characterized by parkinsonism resistant to dopamine therapy, ataxia, autonomic dysfunction, and pathological accumulation of α-synuclein (α-syn) [2,3,4]. This disorder differs from other synucleinopathies in that α-syn accumulates within. 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
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