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.
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Authors | Michelle 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 |
Journal | Proceedings 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 |
PMID | 25316793
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Lipids
- Lysosome-Associated Membrane Glycoproteins
- Neurotoxins
- alpha-Synuclein
- Glucosylceramidase
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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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