title: LIMP-2 expression is critical for β-glucocerebrosidase activity and α-synuclein clearance.
abstract: Mutations within the lysosomal enzyme β-glucocerebrosidase (GC) result in Gaucher disease and represent a major risk factor for developing Parkinson disease (PD). Loss of GC activity leads to accumulation of its substrate glucosylceramide and α-synuclein. Since lysosomal activity of GC is tightly linked to expression of its trafficking receptor, the lysosomal integral membrane protein type-2 (LIMP-2), we studied α-synuclein metabolism in LIMP-2-deficient mice. These mice showed an α-synuclein dosage-dependent phenotype, including severe neurological impairments and premature death. In LIMP-2-deficient brains a significant reduction in GC activity led to lipid storage, disturbed autophagic/lysosomal function, and α-synuclein accumulation mediating neurotoxicity of dopaminergic (DA) neurons, apoptotic cell death, and inflammation. Heterologous expression of LIMP-2 accelerated clearance of overexpressed α-synuclein, possibly through increasing lysosomal GC activity. In surviving DA neurons of human PD midbrain, LIMP-2 levels were increased, probably to compensate for lysosomal GC deficiency. Therefore, we suggest that manipulating LIMP-2 expression to increase lysosomal GC activity is a promising strategy for the treatment of synucleinopathies.
authors.affiliation: Institute of Biochemistry and.
authors.forename: Michelle
authors.initials: M
authors.lastname: Rothaug
authors.affiliation: Institute of Biochemistry and.
authors.forename: Friederike
authors.initials: F
authors.lastname: Zunke
authors.affiliation: Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Mazzulli
authors.affiliation: Department of Electron Microscopy, Centre for Molecular Neurobiology, and.
authors.forename: Michaela
authors.initials: M
authors.lastname: Schweizer
authors.affiliation: Institute of Neuropathology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany;
authors.forename: Hermann
authors.initials: H
authors.lastname: Altmeppen
authors.affiliation: Anatomical Institute, Christian Albrechts University of Kiel, 24098 Kiel, Germany;
authors.forename: Renate
authors.initials: R
authors.lastname: Lüllmann-Rauch
authors.affiliation: Department of Medical Biochemistry, Academic Medical Centre, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
authors.forename: Wouter W
authors.initials: WW
authors.lastname: Kallemeijn
authors.affiliation: Unidade de Biologia do Lisossoma e do Peroxissoma, Instituto de Biologia Molecular e Celular, 4150-180 Porto, Portugal; and.
authors.forename: Paulo
authors.initials: P
authors.lastname: Gaspar
authors.affiliation: Department of Medical Biochemistry, Academic Medical Centre, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
authors.forename: Johannes M
authors.initials: JM
authors.lastname: Aerts
authors.affiliation: Institute of Neuropathology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany;
authors.forename: Markus
authors.initials: M
authors.lastname: Glatzel
authors.affiliation: Institute of Biochemistry and.
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
authors.affiliation: Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;
authors.forename: Dimitri
authors.initials: D
authors.lastname: Krainc
authors.affiliation: Institute of Biochemistry and Faculty of Chemistry/Biochemistry III, University of Bielefeld, 33615 Bielefeld, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schwake
authors.affiliation: Institute of Biochemistry and jblanz@biochem.uni-kiel.de.
authors.forename: Judith
authors.initials: J
authors.lastname: Blanz
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D001933:Brain Stem / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D005911:Gliosis / Q000150:complications / Q000473:pathology; D005962:Glucosylceramidase / Q000378:metabolism*; D006801:Humans; D008055:Lipids / Q000737:chemistry; D051907:Lysosomal Membrane Proteins / Q000172:deficiency / Q000378:metabolism*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D009498:Neurotoxins / Q000633:toxicity; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D008055:Lipids; D051907:Lysosomal Membrane Proteins; D009498:Neurotoxins; D051844:alpha-Synuclein; D005962:Glucosylceramidase
keywords: AMRF; C57/BL6-J; GD; PME; SCARB2