LIMP-2 expression is critical for β-glucocerebrosidase activity and α-synuclein clearance

Michelle Rothaug, Friederike Zunke, Joseph R. Mazzulli, Michaela Schweizer, Hermann Altmeppen, Renate Lüllmann-Rauche, Wouter W. Kallemeijn, Paulo Gaspar, Johannes M. Aerts, Markus Glatzel, Paul Saftig, Dimitri Krainc, Michael Schwake, Judith Blanz*

*Corresponding author for this work

Research output: Contribution to journalArticle

50 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)15573-15578
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number43
DOIs
StatePublished - Oct 28 2014

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Synucleins
Lysosome-Associated Membrane Glycoproteins
Glucosylceramidase
Gaucher Disease
Dopaminergic Neurons
Parkinson Disease
Glucosylceramides
Premature Mortality
Mesencephalon
Cell Death
Inflammation
Phenotype
Lipids
Mutation
Brain
Enzymes

Keywords

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

ASJC Scopus subject areas

  • General

Cite this

Rothaug, Michelle ; Zunke, Friederike ; Mazzulli, Joseph R. ; Schweizer, Michaela ; Altmeppen, Hermann ; Lüllmann-Rauche, Renate ; Kallemeijn, Wouter W. ; Gaspar, Paulo ; Aerts, Johannes M. ; Glatzel, Markus ; Saftig, Paul ; Krainc, Dimitri ; Schwake, Michael ; Blanz, Judith. / LIMP-2 expression is critical for β-glucocerebrosidase activity and α-synuclein clearance. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 43. pp. 15573-15578.
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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.",
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author = "Michelle Rothaug and Friederike Zunke and Mazzulli, {Joseph R.} and Michaela Schweizer and Hermann Altmeppen and Renate L{\"u}llmann-Rauche 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",
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Rothaug, M, Zunke, F, Mazzulli, JR, Schweizer, M, Altmeppen, H, Lüllmann-Rauche, 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', Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 43, pp. 15573-15578. https://doi.org/10.1073/pnas.1405700111

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-Rauche, Renate; Kallemeijn, Wouter W.; Gaspar, Paulo; Aerts, Johannes M.; Glatzel, Markus; Saftig, Paul; Krainc, Dimitri; Schwake, Michael; Blanz, Judith.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 43, 28.10.2014, p. 15573-15578.

Research output: Contribution to journalArticle

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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-Rauche, 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.

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KW - C57/BL6-J

KW - GD

KW - PME

KW - SCARB2

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