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

Rothaug M, Zunke F, Mazzulli JR, Schweizer M, Altmeppen H, Luellmann-Rauch R, Kallemeijn WW, Gaspar P, Aerts JM, Glatzel M, Saftig P, Krainc D, Schwake M, Blanz J (2014)

Publication Type: Journal article

Publication year: 2014

Journal

Proceedings of the National Academy of Sciences of the United States of America National Academy of Sciences

Book Volume: 111

Pages Range: 15573-15578

Journal Issue: 43

DOI: 10.1073/pnas.1405700111

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 with CRIS profile

Friederike Zunke

Involved external institutions

Christian-Albrechts-Universität zu Kiel DE Germany (DE) Universidade do Porto PT Portugal (PT) University of Amsterdam NL Netherlands (NL) Northwestern University US United States (USA) (US) Universitätsklinikum Hamburg-Eppendorf (UKE) DE Germany (DE)

How to cite

APA:

Rothaug, M., Zunke, F., Mazzulli, J.R., Schweizer, M., Altmeppen, H., Luellmann-Rauch, R.,... Blanz, J. (2014). 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, 111(43), 15573-15578. https://doi.org/10.1073/pnas.1405700111

MLA:

Rothaug, Michelle, et al. "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 111.43 (2014): 15573-15578.

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