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

Rothaug M, Zunke F, Mazzulli JR, Schweizer M, Altmeppen H, Luellmann-Rauch R, Kallemeijn WW, Gaspar P, Aerts JM, Glatzel M, Saftig P, et al. (2014)
Proceedings of the National Academy of Sciences 111(43): 15573-15578.

Journal Article | Published | English

No fulltext has been uploaded

Author
; ; ; ; ; ; ; ; ; ; ;
All
Abstract
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.
Keywords
Publishing Year
ISSN
eISSN
PUB-ID

Cite this

Rothaug M, Zunke F, Mazzulli JR, et al. LIMP-2 expression is critical for beta-glucocerebrosidase activity and alpha-synuclein clearance. Proceedings of the National Academy of Sciences. 2014;111(43):15573-15578.
Rothaug, M., Zunke, F., Mazzulli, J. R., Schweizer, M., Altmeppen, H., Luellmann-Rauch, R., Kallemeijn, W. W., et al. (2014). LIMP-2 expression is critical for beta-glucocerebrosidase activity and alpha-synuclein clearance. Proceedings of the National Academy of Sciences, 111(43), 15573-15578.
Rothaug, M., Zunke, F., Mazzulli, J. R., Schweizer, M., Altmeppen, H., Luellmann-Rauch, R., Kallemeijn, W. W., Gaspar, P., Aerts, J. M., Glatzel, M., et al. (2014). LIMP-2 expression is critical for beta-glucocerebrosidase activity and alpha-synuclein clearance. Proceedings of the National Academy of Sciences 111, 15573-15578.
Rothaug, M., et al., 2014. LIMP-2 expression is critical for beta-glucocerebrosidase activity and alpha-synuclein clearance. Proceedings of the National Academy of Sciences, 111(43), p 15573-15578.
M. Rothaug, et al., “LIMP-2 expression is critical for beta-glucocerebrosidase activity and alpha-synuclein clearance”, Proceedings of the National Academy of Sciences, vol. 111, 2014, pp. 15573-15578.
Rothaug, M., Zunke, F., Mazzulli, J.R., Schweizer, M., Altmeppen, H., Luellmann-Rauch, R., Kallemeijn, W.W., Gaspar, P., Aerts, J.M., Glatzel, M., Saftig, P., Krainc, D., Schwake, M., Blanz, J.: LIMP-2 expression is critical for beta-glucocerebrosidase activity and alpha-synuclein clearance. Proceedings of the National Academy of Sciences. 111, 15573-15578 (2014).
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, and Blanz, Judith. “LIMP-2 expression is critical for beta-glucocerebrosidase activity and alpha-synuclein clearance”. Proceedings of the National Academy of Sciences 111.43 (2014): 15573-15578.
This data publication is cited in the following publications:
This publication cites the following data publications:

9 Citations in Europe PMC

Data provided by Europe PubMed Central.

Analysis of Signaling Endosome Composition and Dynamics Using SILAC in Embryonic Stem Cell-Derived Neurons.
Debaisieux S, Encheva V, Chakravarty P, Snijders AP, Schiavo G., Mol. Cell Proteomics 15(2), 2016
PMID: 26685126
Visualization of Active Glucocerebrosidase in Rodent Brain with High Spatial Resolution following In Situ Labeling with Fluorescent Activity Based Probes.
Herrera Moro Chao D, Kallemeijn WW, Marques AR, Orre M, Ottenhoff R, van Roomen C, Foppen E, Renner MC, Moeton M, van Eijk M, Boot RG, Kamphuis W, Hol EM, Aten J, Overkleeft HS, Kalsbeek A, Aerts JM., PLoS ONE 10(9), 2015
PMID: 26418157
Gaucher-Associated Parkinsonism.
Li Y, Li P, Liang H, Zhao Z, Hashimoto M, Wei J., Cell. Mol. Neurobiol. 35(6), 2015
PMID: 25820783
LAMP-2 deficiency leads to hippocampal dysfunction but normal clearance of neuronal substrates of chaperone-mediated autophagy in a mouse model for Danon disease.
Rothaug M, Stroobants S, Schweizer M, Peters J, Zunke F, Allerding M, D'Hooge R, Saftig P, Blanz J., Acta Neuropathol Commun 3(), 2015
PMID: 25637286
Lysosomal integral membrane protein type-2 (LIMP-2/SCARB2) is a substrate of cathepsin-F, a cysteine protease mutated in type-B-Kufs-disease.
Peters J, Rittger A, Weisner R, Knabbe J, Zunke F, Rothaug M, Damme M, Berkovic SF, Blanz J, Saftig P, Schwake M., Biochem. Biophys. Res. Commun. 457(3), 2015
PMID: 25576872
Models of α-synuclein aggregation in Parkinson's disease.
Giraldez-Perez R, Antolin-Vallespin M, Munoz M, Sanchez-Capelo A., Acta Neuropathol Commun 2(), 2014
PMID: 25497491

51 References

Data provided by Europe PubMed Central.

Reversal of peripheral and central neural storage and ataxia after recombinant enzyme replacement therapy in alpha-mannosidosis mice.
Blanz J, Stroobants S, Lullmann-Rauch R, Morelle W, Ludemann M, D'Hooge R, Reuterwall H, Michalski JC, Fogh J, Andersson C, Saftig P., Hum. Mol. Genet. 17(22), 2008
PMID: 18713755

Export

0 Marked Publications

Open Data PUB

Web of Science

View record in Web of Science®

Sources

PMID: 25316793
PubMed | Europe PMC

Search this title in

Google Scholar