title: Glucosylceramide synthase inhibition alleviates aberrations in synucleinopathy models.
abstract: Mutations in the glucocerebrosidase gene (GBA) confer a heightened risk of developing Parkinson's disease (PD) and other synucleinopathies, resulting in a lower age of onset and exacerbating disease progression. However, the precise mechanisms by which mutations inGBAincrease PD risk and accelerate its progression remain unclear. Here, we investigated the merits of glucosylceramide synthase (GCS) inhibition as a potential treatment for synucleinopathies. Two murine models of synucleinopathy (a Gaucher-related synucleinopathy model,GbaD409V/D409Vand a A53T-α-synuclein overexpressing model harboring wild-type alleles ofGBA,A53T-SNCAmouse model) were exposed to a brain-penetrant GCS inhibitor, GZ667161. Treatment ofGbaD409V/D409Vmice with the GCS inhibitor reduced levels of glucosylceramide and glucosylsphingosine in the central nervous system (CNS), demonstrating target engagement. Remarkably, treatment with GZ667161 slowed the accumulation of hippocampal aggregates of α-synuclein, ubiquitin, and tau, and improved the associated memory deficits. Similarly, prolonged treatment ofA53T-SNCAmice with GZ667161 reduced membrane-associated α-synuclein in the CNS and ameliorated cognitive deficits. The data support the contention that prolonged antagonism of GCS in the CNS can affect α-synuclein processing and improve behavioral outcomes. Hence, inhibition of GCS represents a disease-modifying therapeutic strategy forGBA-related synucleinopathies and conceivably for certain forms of sporadic disease.
authors.affiliation: Neuroscience, Sanofi, Framingham, MA 01701; richard_sidman@hms.harvard.edu pablo.sardi@sanofi.com.|Rare Diseases, Sanofi, Framingham, MA 01701.
authors.forename: S Pablo
authors.initials: SP
authors.lastname: Sardi
authors.affiliation: Neuroscience, Sanofi, Framingham, MA 01701.|Rare Diseases, Sanofi, Framingham, MA 01701.
authors.forename: Catherine
authors.initials: C
authors.lastname: Viel
authors.affiliation: Neuroscience, Sanofi, Framingham, MA 01701.|Rare Diseases, Sanofi, Framingham, MA 01701.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Clarke
authors.affiliation: Rare Diseases, Sanofi, Framingham, MA 01701.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Treleaven
authors.affiliation: Neuroscience, Sanofi, Framingham, MA 01701.|Rare Diseases, Sanofi, Framingham, MA 01701.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Richards
authors.affiliation: Analytical R&D, Sanofi, Waltham, MA 02451.
authors.forename: Hyejung
authors.initials: H
authors.lastname: Park
authors.affiliation: Analytical R&D, Sanofi, Waltham, MA 02451.
authors.forename: Maureen A
authors.initials: MA
authors.lastname: Olszewski
authors.affiliation: Neuroscience, Sanofi, Framingham, MA 01701.|Rare Diseases, Sanofi, Framingham, MA 01701.
authors.forename: James C
authors.initials: JC
authors.lastname: Dodge
authors.affiliation: Rare Diseases, Sanofi, Framingham, MA 01701.
authors.forename: John
authors.initials: J
authors.lastname: Marshall
authors.affiliation: Analytical R&D, Sanofi, Waltham, MA 02451.
authors.forename: Elina
authors.initials: E
authors.lastname: Makino
authors.affiliation: Analytical R&D, Sanofi, Waltham, MA 02451.
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215 richard_sidman@hms.harvard.edu pablo.sardi@sanofi.com.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Sidman
authors.affiliation: Rare Diseases, Sanofi, Framingham, MA 01701.
authors.forename: Seng H
authors.initials: SH
authors.lastname: Cheng
authors.affiliation: Neuroscience, Sanofi, Framingham, MA 01701.|Rare Diseases, Sanofi, Framingham, MA 01701.
authors.forename: Lamya S
authors.initials: LS
authors.lastname: Shihabuddin
mesh_terms: D000818:Animals; D002219:Carbamates / Q000494:pharmacology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005786:Gene Expression Regulation; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D051379:Mice; D009154:Mutation; D010300:Parkinson Disease / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D066263:Protein Aggregation, Pathological / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D011812:Quinuclidines / Q000494:pharmacology*; D025801:Ubiquitin / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D002219:Carbamates; D004791:Enzyme Inhibitors; D011812:Quinuclidines; D025801:Ubiquitin; D051844:alpha-Synuclein; C000626789:quinuclidin-3-yl-N-(1-(3-(4-fluorophenyl)phenyl)-1-methyl-ethyl)carbamate; D016875:tau Proteins; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase
keywords: GBA mutations; Gaucher disease; Lewy body dementia; Parkinson’s disease; glucosylceramide synthase