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

Michelle Rothaug, Friederike Zunke, Joseph R. Mazzulli, Michaela Schweizer, Hermann Altmeppen, Renate Lüllmann-Rauche, Wouter W. Kallemeijn, Paulo Gaspar, Johannes M. Aerts, Markus Glatzel, Paul Saftig, Dimitri Krainc, Michael Schwake, Judith Blanz*

*Corresponding author for this work

Research output: Contribution to journalArticle

60 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)15573-15578
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number43
DOIs
StatePublished - Oct 28 2014

Keywords

  • AMRF
  • C57/BL6-J
  • GD
  • PME
  • SCARB2

ASJC Scopus subject areas

  • General

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    Rothaug, M., Zunke, F., Mazzulli, J. R., Schweizer, M., Altmeppen, H., Lüllmann-Rauche, R., Kallemeijn, W. W., Gaspar, P., Aerts, J. M., Glatzel, M., Saftig, P., Krainc, D., Schwake, M., & 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