LIMP-2 expression is critical for beta-glucocerebrosidase activity and alpha-synuclein clearance
| Autor: | Paul Saftig, Michael Schwake, Paulo Gaspar, Friederike Zunke, Johannes M. F. G. Aerts, Renate Lüllmann-Rauch, Dimitri Krainc, Hermann C. Altmeppen, Wouter W. Kallemeijn, Michelle Rothaug, Joseph R. Mazzulli, Michaela Schweizer, Markus Glatzel, Judith Blanz |
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| Přispěvatelé: | Medical Biochemistry, ACS - Amsterdam Cardiovascular Sciences, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism |
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Neurotoxins
Apoptosis Inflammation Biology Autophagy medicine Animals Humans AMRF Gliosis PME Receptor Neurons Synucleinopathies Multidisciplinary GD Dopaminergic Neurotoxicity Lysosome-Associated Membrane Glycoproteins Biological Sciences medicine.disease Lipids Phenotype Cell biology Mice Inbred C57BL SCARB2 nervous system alpha-Synuclein Glucosylceramidase Heterologous expression medicine.symptom Lysosomes C57/BL6-J Brain Stem |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America, 111(43), 15573-15578. National Academy of Sciences Proceedings of the National Academy of Sciences of the United States of America Proceedings of the National Academy of Sciences of the United States of America, 111(43), 15573-15578 |
| ISSN: | 0027-8424 |
| Popis: | Mutations within the lysosomal enzyme beta-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 alpha-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 alpha-synuclein metabolism in LIMP-2-deficient mice. These mice showed an alpha-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 alpha-synuclein accumulation mediating neurotoxicity of dopaminergic (DA) neurons, apoptotic cell death, and inflammation. Heterologous expression of LIMP-2 accelerated clearance of overexpressed alpha-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. |
| Databáze: | OpenAIRE |
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