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LIMP-2 deficiency-associated glycolipid abnormalities in mice

LIMP-2 deficiency-associated glycolipid abnormalities in mice

Paulo Gaspar ¹, André R A Marques ², Maria J Ferraz ³, Markus Damme ⁴, Gertjan Kramer ², Mina Mirzaian ⁵, Marion Gijbels ², Roelof Ottenhoff ², Cindy van Roomen ², Herman S Overkleeft ⁶, Michael Schwake ⁷, Saskia Heybrock ⁴, Maria Carmo Macário ⁸, Paul Saftig ⁴, Johannes M Aerts ³

Paulo Gaspar ¹, André R A Marques ², Maria J Ferraz ³

¹Department of Medical Biochemistry, Academic Medical Center, Amsterdam, the Netherlands; Organelle Biogenesis & Function Group, Instituto de Investigação e Inovação em Saúde and Institute of Molecular and Cell Biology, Universidade do Porto, Porto, Portugal; Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal.
²Department of Medical Biochemistry, Academic Medical Center, Amsterdam, the Netherlands.
³Department of Medical Biochemistry, Academic Medical Center, Amsterdam, the Netherlands; Department of Medical Biochemistry, Leiden Institute of Chemistry, Leiden University, the Netherlands.
⁴Department of Biochemistry, Christian-Albrecht-University of Kiel, Kiel, Germany.
⁵Department of Medical Biochemistry, Leiden Institute of Chemistry, Leiden University, the Netherlands.
⁶Department of Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, the Netherlands.
⁷Department of Chemistry, Biochemistry III, Bielefeld, Germany.
⁸Neurology Department, Coimbra Hospital and University Center, Coimbra, Portugal.

⁰Department of Medical Biochemistry, Academic Medical Center, Amsterdam, the Netherlands; Organelle Biogenesis & Function Group, Instituto de Investigação e Inovação em Saúde and Institute of Molecular and Cell Biology, Universidade do Porto, Porto, Portugal; Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal.

Biochimica Et Biophysica Acta. Molecular and Cell Biology of Lipids +

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July 10, 2025

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View abstract on PubMed

Summary

This summary is machine-generated.

Lysosomal integral membrane protein type 2 (LIMP-2) deficiency reduces glucocerebrosidase (GCase) levels, causing distinct symptoms from Gaucher disease. LIMP-2 deficiency prevents glucosylceramide accumulation by altering metabolite levels.

Area Of Science

Cell Biology
Biochemistry
Genetics

Background

Glucocerebrosidase (GCase) degrades glucosylceramide (GlcCer) in lysosomes.
GCase deficiency causes Gaucher disease (GD), characterized by organ enlargement.
Lysosomal integral membrane protein type 2 (LIMP-2) facilitates GCase transport to lysosomes.

Purpose Of The Study

Investigate the differing pathologies of GD and LIMP-2 deficiency (Action Myoclonic Renal Failure Syndrome - AMRF).
Determine the impact of LIMP-2 deficiency on lysosomal enzymes and glycosphingolipid metabolism.

Main Methods

Analysis of lysosomal enzymes and GCase activity in Limp2-/- mice tissues and leukocytes.
Measurement of glucosylceramide (GlcCer), glucosylsphingosine (GlcSph), and glucosylated cholesterol (GlcChol) levels.
Biochemical analysis of isolated lysosomes and tritosomes from Limp2-/- hepatocytes.

Main Results

Limp2-/- mice exhibit variable GCase deficiency but not GD.
GCase deficiency in tissues correlates with increased GlcSph and GlcChol, not GlcCer.
Lysosomes and tritosomes from Limp2-/- hepatocytes show elevated GlcSph and GlcChol.

Conclusions

LIMP-2 plays a crucial role in maintaining glycosphingolipid homeostasis.
LIMP-2 deficiency prevents GlcCer accumulation despite reduced GCase levels.
The distinct metabolite profile in LIMP-2 deficiency explains its unique symptomatology compared to GD.

Keywords:

Cerebrosides Cholesterol GBA Gaucher's disease Glucocerebrosidase Glucosylceramide Glucosylcholesterol LIMP-2 Lysosomes Mass spectrometry SCARB2

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