title: Glucocerebrosidase modulates cognitive and motor activities in murine models of Parkinson's disease.
abstract: Mutations in GBA1, the gene encoding glucocerebrosidase, are associated with an enhanced risk of developing synucleinopathies such as Parkinson's disease (PD) and dementia with Lewy bodies. A higher prevalence and increased severity of motor and non-motor symptoms is observed in PD patients harboring mutant GBA1 alleles, suggesting a link between the gene or gene product and disease development. Interestingly, PD patients without mutations in GBA1 also exhibit lower levels of glucocerebrosidase activity in the central nervous system (CNS), implicating this lysosomal enzyme in disease pathogenesis. Here, we investigated whether modulation of glucocerebrosidase activity in murine models of synucleinopathy (expressing wild type Gba1) affected α-synuclein accumulation and behavioral phenotypes. Partial inhibition of glucocerebrosidase activity in PrP-A53T-SNCA mice using the covalent inhibitor conduritol-B-epoxide induced a profound increase in soluble α-synuclein in the CNS and exacerbated cognitive and motor deficits. Conversely, augmenting glucocerebrosidase activity in the Thy1-SNCA mouse model of PD delayed the progression of synucleinopathy. Adeno-associated virus-mediated expression of glucocerebrosidase in the Thy1-SNCA mouse striatum led to decrease in the levels of the proteinase K-resistant fraction of α-synuclein, amelioration of behavioral aberrations and protection from loss of striatal dopaminergic markers. These data indicate that increasing glucocerebrosidase activity can influence α-synuclein homeostasis, thereby reducing the progression of synucleinopathies. This study provides robust in vivo evidence that augmentation of CNS glucocerebrosidase activity is a potential therapeutic strategy for PD, regardless of the mutation status of GBA1.
authors.affiliation: Neuroscience Department, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Rockenstein
authors.affiliation: Sanofi Genzyme, Framingham, MA 01701, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Clarke
authors.affiliation: Sanofi Genzyme, Framingham, MA 01701, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Viel
authors.affiliation: Sanofi Genzyme, Framingham, MA 01701, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Panarello
authors.affiliation: Sanofi Genzyme, Framingham, MA 01701, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Treleaven
authors.affiliation: Neuroscience Department, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Changyoun
authors.initials: C
authors.lastname: Kim
authors.affiliation: Neuroscience Department, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Spencer
authors.affiliation: Neuroscience Department, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Adame
authors.affiliation: Sanofi Genzyme, Framingham, MA 01701, USA.
authors.forename: Hyejung
authors.initials: H
authors.lastname: Park
authors.affiliation: Sanofi Genzyme, Framingham, MA 01701, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Dodge
authors.affiliation: Sanofi Genzyme, Framingham, MA 01701, USA.
authors.forename: Seng H
authors.initials: SH
authors.lastname: Cheng
authors.affiliation: Sanofi Genzyme, Framingham, MA 01701, USA.
authors.forename: Lamya S
authors.initials: LS
authors.lastname: Shihabuddin
authors.affiliation: Neuroscience Department, University of California San Diego, La Jolla, CA 92093, USA.|Pathology Department, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: E
authors.initials: E
authors.lastname: Masliah
authors.affiliation: Sanofi Genzyme, Framingham, MA 01701, USA pablo.sardi@genzyme.com.
authors.forename: S Pablo
authors.initials: SP
authors.lastname: Sardi
mesh_terms: D000818:Animals; D003071:Cognition / Q000187:drug effects; D004195:Disease Models, Animal; D004298:Dopamine; D005776:Gaucher Disease / Q000235:genetics; D015870:Gene Expression; D005962:Glucosylceramidase / Q000235:genetics / Q000378:metabolism* / Q000502:physiology* / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009154:Mutation; D010300:Parkinson Disease / Q000188:drug therapy / Q000235:genetics; D051844:alpha-Synuclein / Q000134:cerebrospinal fluid / Q000378:metabolism
chemical_list: D051844:alpha-Synuclein; D005962:Glucosylceramidase; D004298:Dopamine