LIMP-2 expression is critical for β-glucocerebrosidase activity and α-synuclein clearance
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LIMP-2 expression is critical for β-glucocerebrosidase activity and α-synuclein clearance. / Rothaug, Michelle; Zunke, Friederike; Mazzulli, Joseph R; Schweizer, Michaela; Altmeppen, Hermann; Lüllmann-Rauch, Renate; Kallemeijn, Wouter W; Gaspar, Paulo; Aerts, Johannes M; Glatzel, Markus; Saftig, Paul; Krainc, Dimitri; Schwake, Michael; Blanz, Judith.
in: P NATL ACAD SCI USA, Jahrgang 111, Nr. 43, 28.10.2014, S. 15573-8.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - LIMP-2 expression is critical for β-glucocerebrosidase activity and α-synuclein clearance
AU - Rothaug, Michelle
AU - Zunke, Friederike
AU - Mazzulli, Joseph R
AU - Schweizer, Michaela
AU - Altmeppen, Hermann
AU - Lüllmann-Rauch, Renate
AU - Kallemeijn, Wouter W
AU - Gaspar, Paulo
AU - Aerts, Johannes M
AU - Glatzel, Markus
AU - Saftig, Paul
AU - Krainc, Dimitri
AU - Schwake, Michael
AU - Blanz, Judith
PY - 2014/10/28
Y1 - 2014/10/28
N2 - 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.
AB - 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.
U2 - 10.1073/pnas.1405700111
DO - 10.1073/pnas.1405700111
M3 - SCORING: Journal article
C2 - 25316793
VL - 111
SP - 15573
EP - 15578
JO - P NATL ACAD SCI USA
JF - P NATL ACAD SCI USA
SN - 0027-8424
IS - 43
ER -