title: Neuroinflammation and α-synuclein accumulation in response to glucocerebrosidase deficiency are accompanied by synaptic dysfunction.
abstract: Clinical, epidemiological and experimental studies confirm a connection between the common degenerative movement disorder Parkinson's disease (PD) that affects over 1 million individuals, and Gaucher disease, the most prevalent lysosomal storage disorder. Recently, human imaging studies have implicated impaired striatal dopaminergic neurotransmission in early PD pathogenesis in the context of Gaucher disease mutations, but the underlying mechanisms have yet to be characterized. In this report we describe and characterize two novel long-lived transgenic mouse models of Gba deficiency, along with a subchronic conduritol-ß-epoxide (CBE) exposure paradigm. All three murine models revealed striking glial activation within nigrostriatal pathways, accompanied by abnormal α-synuclein accumulation. Importantly, the CBE-induced, pharmacological Gaucher mouse model replicated this change in dopamine neurotransmission, revealing a markedly reduced evoked striatal dopamine release (approximately 2-fold) that indicates synaptic dysfunction. Other changes in synaptic plasticity markers, including microRNA profile and a 24.9% reduction in post-synaptic density size, were concomitant with diminished evoked dopamine release following CBE exposure. These studies afford new insights into the mechanisms underlying the Parkinson's-Gaucher disease connection, and into the physiological impact of related abnormal α-synuclein accumulation and neuroinflammation on nigrostriatal dopaminergic neurotransmission.
authors.affiliation: Lysosomal Disorders Treatment and Research Program, Clinical Labs, University of Massachusetts Medical School, Worcester, MA 01545, USA; Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA 01545, USA; Clinical Neuroscience Branch, IRP, NIMH, Bethesda, MD 20892, USA.
authors.forename: Edward I
authors.initials: EI
authors.lastname: Ginns
authors.affiliation: Center for Health Sciences, Biosciences Division, SRI International, Menlo Park, CA 94025, USA.
authors.forename: Sally K-K
authors.initials: SK
authors.lastname: Mak
authors.affiliation: Center for Health Sciences, Biosciences Division, SRI International, Menlo Park, CA 94025, USA.
authors.forename: Novie
authors.initials: N
authors.lastname: Ko
authors.affiliation: Lysosomal Disorders Treatment and Research Program, Clinical Labs, University of Massachusetts Medical School, Worcester, MA 01545, USA.
authors.forename: Juliane
authors.initials: J
authors.lastname: Karlgren
authors.affiliation: Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA 01545, USA.
authors.forename: Schahram
authors.initials: S
authors.lastname: Akbarian
authors.affiliation: Center for Health Sciences, Biosciences Division, SRI International, Menlo Park, CA 94025, USA.
authors.forename: Vivian P
authors.initials: VP
authors.lastname: Chou
authors.affiliation: Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA 01545, USA.
authors.forename: Yin
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Lysosomal Disorders Treatment and Research Program, Clinical Labs, University of Massachusetts Medical School, Worcester, MA 01545, USA; Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA 01545, USA.
authors.forename: Arlene
authors.initials: A
authors.lastname: Lim
authors.affiliation: Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, CA 94025, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Samuelsson
authors.affiliation: Clinical Neuroscience Branch, IRP, NIMH, Bethesda, MD 20892, USA.
authors.forename: Mary L
authors.initials: ML
authors.lastname: LaMarca
authors.affiliation: Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, CA 94025, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Vazquez-DeRose
authors.affiliation: Center for Health Sciences, Biosciences Division, SRI International, Menlo Park, CA 94025, USA. Electronic address: amy.manningbog@sri.com.
authors.forename: Amy B
authors.initials: AB
authors.lastname: Manning-Boğ
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D019054:Evoked Potentials, Motor; D005260:Female; D005776:Gaucher Disease / Q000201:enzymology / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D005962:Glucosylceramidase; D006801:Humans; D007249:Inflammation; D007294:Inositol / Q000008:administration & dosage / Q000031:analogs & derivatives; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009473:Neuronal Plasticity; D010300:Parkinson Disease / Q000201:enzymology / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D013569:Synapses / Q000201:enzymology / Q000473:pathology*; D009435:Synaptic Transmission; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D035683:MicroRNAs; D051844:alpha-Synuclein; D007294:Inositol; D005962:Glucosylceramidase; C011423:conduritol epoxide; D004298:Dopamine
keywords: Gaucher disease; Glucocerebrosidase; Neuroinflammation; Parkinson's disease; Synaptic dysfunction; α-Synuclein