title: A brain-targeted, modified neurosin (kallikrein-6) reduces α-synuclein accumulation in a mouse model of multiple system atrophy.
abstract: 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.
  
  
  CONCLUSIONS
  Thus, the modified, brain-targeted neurosin may warrant further investigation as potential therapy for MSA.
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, CA, 92093, USA. b1spencer@ucsd.edu.
authors.forename: Brian
authors.initials: B
authors.lastname: Spencer
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, CA, 92093, USA. evaleramartin@ucsd.edu.
authors.forename: Elvira
authors.initials: E
authors.lastname: Valera
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, CA, 92093, USA. erockenstein@ucsd.edu.
authors.forename: Edward
authors.initials: E
authors.lastname: Rockenstein
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, CA, 92093, USA. mtrejo@ucsd.edu.
authors.forename: Margarita
authors.initials: M
authors.lastname: Trejo-Morales
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, CA, 92093, USA. asadame@ucsd.edu.
authors.forename: Anthony
authors.initials: A
authors.lastname: Adame
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, CA, 92093, USA. emasliah@ucsd.edu.|Department of Pathology, University of California, San Diego, La Jolla, CA, 92093, USA. emasliah@ucsd.edu.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001522:Behavior, Animal; D002478:Cells, Cultured; D004195:Disease Models, Animal; D007610:Kallikreins / Q000378:metabolism*; D051379:Mice; D019578:Multiple System Atrophy / Q000235:genetics / Q000378:metabolism*; D009836:Oligodendroglia / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein; D007610:Kallikreins; C491223:Prss18 protein, mouse