Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 43, Pages 15573-15578Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1405700111
Keywords
SCARB2; AMRF; PME; GD; C57/BL6-J
Categories
Funding
- Research Training Group [GRK1459]
- Deutsche Forschungsgemeinschaft (DFG) [Schw 866/4-1]
- European Union [EU/ALPHA-MAN 261331]
- Boehringer Ingelheim Fonds
- National Institutes of Health [R01NS076054]
- Fundacao para a Ciencia e Tecnologia [SFRH/BD/72862/2010]
- Fundação para a Ciência e a Tecnologia [SFRH/BD/72862/2010] Funding Source: FCT
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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.
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