title: Glucocerebrosidase 1 deficient Danio rerio mirror key pathological aspects of human Gaucher disease and provide evidence of early microglial activation preceding alpha-synuclein-independent neuronal cell death.
abstract: Autosomal recessively inherited glucocerebrosidase 1 (GBA1) mutations cause the lysosomal storage disorder Gaucher's disease (GD). Heterozygous GBA1 mutations (GBA1(+/-)) are the most common risk factor for Parkinson's disease (PD). Previous studies typically focused on the interaction between the reduction of glucocerebrosidase (enzymatic) activity in GBA1(+/-) carriers and alpha-synuclein-mediated neurotoxicity. However, it is unclear whether other mechanisms also contribute to the increased risk of PD in GBA1(+/-) carriers. The zebrafish genome does not contain alpha-synuclein (SNCA), thus providing a unique opportunity to study pathogenic mechanisms unrelated to alpha-synuclein toxicity. Here we describe a mutant zebrafish line created by TALEN genome editing carrying a 23 bp deletion in gba1 (gba1(c.1276_1298del)), the zebrafish orthologue of human GBA1. Marked sphingolipid accumulation was already detected at 5 days post-fertilization with accompanying microglial activation and early, sustained up-regulation of miR-155, a master regulator of inflammation. gba1(c.1276_1298del) mutant zebrafish developed a rapidly worsening phenotype from 8 weeks onwards with striking reduction in motor activity by 12 weeks. Histopathologically, we observed marked Gaucher cell invasion of the brain and other organs. Dopaminergic neuronal cell count was normal through development but reduced by >30% at 12 weeks in the presence of ubiquitin-positive, intra-neuronal inclusions. This gba1(c.1276_1298del) zebrafish line is the first viable vertebrate model sharing key pathological features of GD in both neuronal and non-neuronal tissue. Our study also provides evidence for early microglial activation prior to alpha-synuclein-independent neuronal cell death in GBA1 deficiency and suggests upregulation of miR-155 as a common denominator across different neurodegenerative disorders.
authors.affiliation: The Bateson Centre, Sheffield Institute for Translational Neuroscience (SITraN).
authors.forename: Marcus
authors.initials: M
authors.lastname: Keatinge
authors.affiliation: Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, USA.
authors.forename: Hai
authors.initials: H
authors.lastname: Bui
authors.affiliation: TNO, Zeist, The Netherlands.
authors.forename: Aswin
authors.initials: A
authors.lastname: Menke
authors.affiliation: Neuroscience Center and Department of Anatomy, University of Helsinki, Finland.
authors.forename: Yu-Chia
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Laboratory of Mitochondrial Biogenesis, International Institute of Molecular and Cell Biology, Warsaw, Poland.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Sokol
authors.affiliation: Pittsburgh Institute for Neurodegenerative Diseases and Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Bai
authors.affiliation: The Bateson Centre.
authors.forename: Felix
authors.initials: F
authors.lastname: Ellett
authors.affiliation: The Bateson Centre, Sheffield Institute for Translational Neuroscience (SITraN).
authors.forename: Marc
authors.initials: M
authors.lastname: Da Costa
authors.affiliation: Molecular and Genetics Unit, University College London Institute of Child Health, Enzyme Unit and Metabolic Unit, Chemical Pathology, Great Ormond Street Hospital, London, UK.
authors.forename: Derek
authors.initials: D
authors.lastname: Burke
authors.affiliation: Department of Clinical Neurosciences, University College London Institute of Neurology, London, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Gegg
authors.affiliation: The Bateson Centre, Sheffield Institute for Translational Neuroscience (SITraN).
authors.forename: Lisa
authors.initials: L
authors.lastname: Trollope
authors.affiliation: The Bateson Centre, Sheffield Institute for Translational Neuroscience (SITraN).
authors.forename: Thomas
authors.initials: T
authors.lastname: Payne
authors.affiliation: The Bateson Centre, Sheffield Institute for Translational Neuroscience (SITraN).
authors.forename: Aimee
authors.initials: A
authors.lastname: McTighe
authors.affiliation: Sheffield Institute for Translational Neuroscience (SITraN).
authors.forename: Heather
authors.initials: H
authors.lastname: Mortiboys
authors.affiliation: Department of Medical Genetics, Cambridge Institute for Medical Research University of Cambridge, Cambridge, UK and.
authors.forename: Sarah
authors.initials: S
authors.lastname: de Jager
authors.affiliation: Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, USA.
authors.forename: Hugh
authors.initials: H
authors.lastname: Nuthall
authors.affiliation: Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, USA.
authors.forename: Ming-Shang
authors.initials: MS
authors.lastname: Kuo
authors.affiliation: Department of Medical Genetics, Cambridge Institute for Medical Research University of Cambridge, Cambridge, UK and.
authors.forename: Angeleen
authors.initials: A
authors.lastname: Fleming
authors.affiliation: Department of Clinical Neurosciences, University College London Institute of Neurology, London, UK.
authors.forename: Anthony H V
authors.initials: AH
authors.lastname: Schapira
authors.affiliation: The Bateson Centre, Department of Infection and Immunity, University of Sheffield, Sheffield, UK.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Renshaw
authors.affiliation: Sheffield Institute for Translational Neuroscience (SITraN).
authors.forename: J Robin
authors.initials: JR
authors.lastname: Highley
authors.affiliation: Laboratory of Mitochondrial Biogenesis, International Institute of Molecular and Cell Biology, Warsaw, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Chacinska
authors.affiliation: Neuroscience Center and Department of Anatomy, University of Helsinki, Finland.
authors.forename: Pertti
authors.initials: P
authors.lastname: Panula
authors.affiliation: Pittsburgh Institute for Neurodegenerative Diseases and Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, USA.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Burton
authors.affiliation: Eli Lilly and Company Limited, Surrey, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: O'Neill
authors.affiliation: The Bateson Centre, Sheffield Institute for Translational Neuroscience (SITraN), o.bandmann@sheffield.ac.uk.
authors.forename: Oliver
authors.initials: O
authors.lastname: Bandmann
mesh_terms: D000818:Animals; D016923:Cell Death; D004195:Disease Models, Animal; D005776:Gaucher Disease / Q000235:genetics* / Q000473:pathology; D005962:Glucosylceramidase / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics; D017628:Microglia / Q000378:metabolism / Q000502:physiology; D009474:Neurons / Q000378:metabolism / Q000473:pathology* / Q000502:physiology; D017384:Sequence Deletion; D015854:Up-Regulation; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics*; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: C000610068:MIRN155 microRNA, zebrafish; D035683:MicroRNAs; D029961:Zebrafish Proteins; D051844:alpha-Synuclein; D005962:Glucosylceramidase; C000610067:gba protein, zebrafish