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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.
AuthorsMichelle Rothaug, Friederike Zunke, Joseph R Mazzulli, Michaela Schweizer, Hermann Altmeppen, Renate Lüllmann-Rauch, Wouter W Kallemeijn, Paulo Gaspar, Johannes M Aerts, Markus Glatzel, Paul Saftig, Dimitri Krainc, Michael Schwake, Judith Blanz
JournalProceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 43 Pg. 15573-8 (Oct 28 2014) ISSN: 1091-6490 [Electronic] United States
PMID25316793 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Lipids
  • Lysosome-Associated Membrane Glycoproteins
  • Neurotoxins
  • alpha-Synuclein
  • Glucosylceramidase
Topics
  • 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)

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