title: Lentivirus mediated delivery of neurosin promotes clearance of wild-type α-synuclein and reduces the pathology in an α-synuclein model of LBD.
abstract: Neurosin is a predominant serine protease in the central nervous system (CNS) and has been shown to play a role in the clearance of α-synuclein (α-syn) which is centrally involved in the pathogenesis of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Although it has been previously shown that neurosin and α-syn colocalize and that neurosin degrades α-syn aggregates in vitro, it is not clear if neurosin is dysregulated in the brains of patients with PD/DLB and to what extent delivery of neurosin into the CNS might ameliorate the deficits associated with α-syn accumulation in vivo. We analyzed the levels of neurosin in the brains of patients with PD/DLB and in α-syn transgenic (tg) models. With increased accumulation of α-syn, we observed decreased neurosin expression. Lentiviral vector (LV) driven expression of neurosin in neuronal cell cultures reduced the accumulation of wild type but not A53T α-syn and prevented α-syn associated toxicity. Neuropathological analysis following delivery of LV-Neurosin to α-syn tg mice resulted in reduced accumulation of α-syn and reversal of neurodegenerative alterations in wild type but not A53T α-syn tg mice. Therefore, viral vector driven expression of neurosin may warrant further investigation as a potential therapeutic tool for DLB.
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, California 92093-0624, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Spencer
authors.forename: Sarah
authors.initials: S
authors.lastname: Michael
authors.forename: Jay
authors.initials: J
authors.lastname: Shen
authors.forename: Kori
authors.initials: K
authors.lastname: Kosberg
authors.forename: Edward
authors.initials: E
authors.lastname: Rockenstein
authors.forename: Christina
authors.initials: C
authors.lastname: Patrick
authors.forename: Anthony
authors.initials: A
authors.lastname: Adame
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004195:Disease Models, Animal; D006801:Humans; D007150:Immunohistochemistry; D007610:Kallikreins / Q000235:genetics*; D016086:Lentivirus / Q000235:genetics*; D020961:Lewy Body Disease / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009474:Neurons / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D051844:alpha-Synuclein; C103551:KLK6 protein, human; D007610:Kallikreins; C491223:Prss18 protein, mouse