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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, Vol. 111, No. 43, 28.10.2014, p. 15573-8.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Rothaug, M, Zunke, F, Mazzulli, JR, Schweizer, M, Altmeppen, H, Lüllmann-Rauch, R, Kallemeijn, WW, Gaspar, P, Aerts, JM, Glatzel, M, Saftig, P, Krainc, D, Schwake, M & Blanz, J 2014, 'LIMP-2 expression is critical for β-glucocerebrosidase activity and α-synuclein clearance', P NATL ACAD SCI USA, vol. 111, no. 43, pp. 15573-8. https://doi.org/10.1073/pnas.1405700111

APA

Rothaug, M., Zunke, F., Mazzulli, J. R., Schweizer, M., Altmeppen, H., Lüllmann-Rauch, R., Kallemeijn, W. W., Gaspar, P., Aerts, J. M., Glatzel, M., Saftig, P., Krainc, D., Schwake, M., & Blanz, J. (2014). LIMP-2 expression is critical for β-glucocerebrosidase activity and α-synuclein clearance. P NATL ACAD SCI USA, 111(43), 15573-8. https://doi.org/10.1073/pnas.1405700111

Vancouver

Rothaug M, Zunke F, Mazzulli JR, Schweizer M, Altmeppen H, Lüllmann-Rauch R et al. LIMP-2 expression is critical for β-glucocerebrosidase activity and α-synuclein clearance. P NATL ACAD SCI USA. 2014 Oct 28;111(43):15573-8. https://doi.org/10.1073/pnas.1405700111

Bibtex

@article{a2bfb8e7a3e548dbbef699ed0e871da8,
title = "LIMP-2 expression is critical for β-glucocerebrosidase activity and α-synuclein clearance",
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.",
author = "Michelle Rothaug and Friederike Zunke and Mazzulli, {Joseph R} and Michaela Schweizer and Hermann Altmeppen and Renate L{\"u}llmann-Rauch and Kallemeijn, {Wouter W} and Paulo Gaspar and Aerts, {Johannes M} and Markus Glatzel and Paul Saftig and Dimitri Krainc and Michael Schwake and Judith Blanz",
year = "2014",
month = oct,
day = "28",
doi = "10.1073/pnas.1405700111",
language = "English",
volume = "111",
pages = "15573--8",
journal = "P NATL ACAD SCI USA",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "43",

}

RIS

TY - JOUR

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 -