LIMP-2 expression is critical for beta-glucocerebrosidase activity and alpha-synuclein clearance

作者：Rothaug Michelle; Zunke Friederike; Mazzulli Joseph R; Schweizer Michaela; Altmeppen Hermann; Luellmann Rauch Renate; Kallemeijn Wouter W; Gaspar Paulo; Aerts Johannes M; Glatzel Markus; Saftig Paul; Krainc Dimitri; Schwake Michael; Blanz Judith^*

来源：Proceedings of the National Academy of Sciences, 2014, 111(43): 15573-15578.

DOI：10.1073/pnas.1405700111

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

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.

• 出版日期2014-10-28
• 单位西北大学