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PMID: 25316793 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

LIMP-2 expression is critical for β-glucocerebrosidase activity and α-synuclein clearance.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 111 ·No. 43 ·2014-10-28 ·Pages 15573-8

Rothaug M, Zunke F, Mazzulli JR, Schweizer M, Altmeppen H, Lüllmann-Rauch R, Kallemeijn WW, Gaspar P, Aerts JM, Glatzel M, Saftig P, Krainc D, Schwake M, Blanz J

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.

Keywords
AMRF C57/BL6-J GD PME SCARB2
MeSH Terms
Animals Apoptosis/drug effects Autophagy/drug effects Brain Stem/drug effects,enzymology,pathology,ultrastructure Gliosis/complications,pathology Glucosylceramidase/metabolism Humans Lipids/chemistry Lysosome-Associated Membrane Glycoproteins/deficiency,metabolism Lysosomes/drug effects,metabolism,pathology Mice, Inbred C57BL Neurons/drug effects,metabolism,pathology,ultrastructure Neurotoxins/toxicity alpha-Synuclein/metabolism
Chemicals
Lipids Lysosome-Associated Membrane Glycoproteins Neurotoxins alpha-Synuclein Glucosylceramidase
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Rothaug Michelle
Institute of Biochemistry and.
Zunke Friederike
Institute of Biochemistry and.
Mazzulli Joseph R
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;
Schweizer Michaela
Department of Electron Microscopy, Centre for Molecular Neurobiology, and.
Altmeppen Hermann
Institute of Neuropathology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany;
Lüllmann-Rauch Renate
Anatomical Institute, Christian Albrechts University of Kiel, 24098 Kiel, Germany;
Kallemeijn Wouter W
Department of Medical Biochemistry, Academic Medical Centre, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
Gaspar Paulo
Unidade de Biologia do Lisossoma e do Peroxissoma, Instituto de Biologia Molecular e Celular, 4150-180 Porto, Portugal; and.
Aerts Johannes M
Department of Medical Biochemistry, Academic Medical Centre, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
Glatzel Markus
Institute of Neuropathology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany;
Saftig Paul
Institute of Biochemistry and.
Krainc Dimitri
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;
Schwake Michael
Institute of Biochemistry and Faculty of Chemistry/Biochemistry III, University of Bielefeld, 33615 Bielefeld, Germany.
Blanz Judith
Institute of Biochemistry and jblanz@biochem.uni-kiel.de.
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.1405700111
Email
jblanz@biochem.uni-kiel.de
Published
2014-10-28
Epub
2014-00-14
Pages
15573-8
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC4217458
Subset
IM
Grants
NINDS NIH HHS · R01 NS076054 · United States
NINDS NIH HHS · R01NS076054 · United States
External Links
PubMed source DOI: 10.1073/pnas.1405700111 PMC Full Text View journal details
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