Accumulation of bis(monoacylglycero)phosphate and gangliosides in mouse models of neuronal ceroid lipofuscinosis

Sabrina Jabs, Arne Quitsch, Reijo Käkelä, Bettina Koch, Jaana Tyynelä, Helmut Brade, Markus Glatzel, Steven U. Walkley, Paul Saftig, Marie T. Vanier, Thomas Braulke

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

The neuronal ceroid lipofuscinoses comprise a group of inherited severe neurodegenerative lysosomal disorders characterized by lysosomal dysfunction and massive accumulation of fluorescent lipopigments and aggregated proteins. To examine the role of lipids in neurodegenerative processes of these diseases, we analysed phospho- and glycolipids in the brains of ctsd-/- and nclf mice, disease models of cathepsin D and CLN6 deficiency, respectively. Both ctsd-/- and nclf mice exhibited increased levels of GM2 and GM3 gangliosides. Immunohistochemically GM2 and GM3 staining was found preferentially in neurons and glial cells, respectively, of ctsd-/- mice. Of particular note, a 20-fold elevation of the unusual lysophospholipid bis(monoacylglycero)phosphate was specifically detected in the brain of ctsd-/- mice accompanied with sporadic accumulation of unesterified cholesterol in distinct cells. The impaired processing of the sphingolipid activator protein precursor, an in vitro cathepsin D substrate, in the brain of ctsd-/- mice may provide the mechanistic link to the storage of lipids. These studies show for the first time that cathepsin D regulates the lysosomal phospho- and glycosphingolipid metabolism suggesting that defects in the composition, trafficking and/or recycling of membrane components along the late endocytic pathway may be critical for the pathogenesis of early onset neuronal ceroid lipofuscinoses.

Original languageEnglish (US)
Pages (from-to)1415-1425
Number of pages11
JournalJournal of Neurochemistry
Volume106
Issue number3
DOIs
StatePublished - Aug 2008

Fingerprint

Ceroid
Neuronal Ceroid-Lipofuscinoses
Cathepsin D
Gangliosides
Brain
Sphingolipid Activator Proteins
G(M2) Ganglioside
G(M3) Ganglioside
Lysophospholipids
Lipids
Glycosphingolipids
Protein Precursors
Neurodegenerative Diseases
Glycolipids
Metabolism
Neurons
Recycling
Phospholipids
Cholesterol
Membranes

Keywords

  • Bis(monoacylglycero)phosphate
  • Cathepsin D
  • GM2 ganglioside
  • Lysosomes
  • Mouse brain
  • Neuronal ceroid lipofuscinosis

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Accumulation of bis(monoacylglycero)phosphate and gangliosides in mouse models of neuronal ceroid lipofuscinosis. / Jabs, Sabrina; Quitsch, Arne; Käkelä, Reijo; Koch, Bettina; Tyynelä, Jaana; Brade, Helmut; Glatzel, Markus; Walkley, Steven U.; Saftig, Paul; Vanier, Marie T.; Braulke, Thomas.

In: Journal of Neurochemistry, Vol. 106, No. 3, 08.2008, p. 1415-1425.

Research output: Contribution to journalArticle

Jabs, S, Quitsch, A, Käkelä, R, Koch, B, Tyynelä, J, Brade, H, Glatzel, M, Walkley, SU, Saftig, P, Vanier, MT & Braulke, T 2008, 'Accumulation of bis(monoacylglycero)phosphate and gangliosides in mouse models of neuronal ceroid lipofuscinosis', Journal of Neurochemistry, vol. 106, no. 3, pp. 1415-1425. https://doi.org/10.1111/j.1471-4159.2008.05497.x
Jabs, Sabrina ; Quitsch, Arne ; Käkelä, Reijo ; Koch, Bettina ; Tyynelä, Jaana ; Brade, Helmut ; Glatzel, Markus ; Walkley, Steven U. ; Saftig, Paul ; Vanier, Marie T. ; Braulke, Thomas. / Accumulation of bis(monoacylglycero)phosphate and gangliosides in mouse models of neuronal ceroid lipofuscinosis. In: Journal of Neurochemistry. 2008 ; Vol. 106, No. 3. pp. 1415-1425.
@article{eae3489db6d246918c3e5c683916904a,
title = "Accumulation of bis(monoacylglycero)phosphate and gangliosides in mouse models of neuronal ceroid lipofuscinosis",
abstract = "The neuronal ceroid lipofuscinoses comprise a group of inherited severe neurodegenerative lysosomal disorders characterized by lysosomal dysfunction and massive accumulation of fluorescent lipopigments and aggregated proteins. To examine the role of lipids in neurodegenerative processes of these diseases, we analysed phospho- and glycolipids in the brains of ctsd-/- and nclf mice, disease models of cathepsin D and CLN6 deficiency, respectively. Both ctsd-/- and nclf mice exhibited increased levels of GM2 and GM3 gangliosides. Immunohistochemically GM2 and GM3 staining was found preferentially in neurons and glial cells, respectively, of ctsd-/- mice. Of particular note, a 20-fold elevation of the unusual lysophospholipid bis(monoacylglycero)phosphate was specifically detected in the brain of ctsd-/- mice accompanied with sporadic accumulation of unesterified cholesterol in distinct cells. The impaired processing of the sphingolipid activator protein precursor, an in vitro cathepsin D substrate, in the brain of ctsd-/- mice may provide the mechanistic link to the storage of lipids. These studies show for the first time that cathepsin D regulates the lysosomal phospho- and glycosphingolipid metabolism suggesting that defects in the composition, trafficking and/or recycling of membrane components along the late endocytic pathway may be critical for the pathogenesis of early onset neuronal ceroid lipofuscinoses.",
keywords = "Bis(monoacylglycero)phosphate, Cathepsin D, GM2 ganglioside, Lysosomes, Mouse brain, Neuronal ceroid lipofuscinosis",
author = "Sabrina Jabs and Arne Quitsch and Reijo K{\"a}kel{\"a} and Bettina Koch and Jaana Tyynel{\"a} and Helmut Brade and Markus Glatzel and Walkley, {Steven U.} and Paul Saftig and Vanier, {Marie T.} and Thomas Braulke",
year = "2008",
month = "8",
doi = "10.1111/j.1471-4159.2008.05497.x",
language = "English (US)",
volume = "106",
pages = "1415--1425",
journal = "Journal of Neurochemistry",
issn = "0022-3042",
publisher = "Wiley-Blackwell",
number = "3",

}

TY - JOUR

T1 - Accumulation of bis(monoacylglycero)phosphate and gangliosides in mouse models of neuronal ceroid lipofuscinosis

AU - Jabs, Sabrina

AU - Quitsch, Arne

AU - Käkelä, Reijo

AU - Koch, Bettina

AU - Tyynelä, Jaana

AU - Brade, Helmut

AU - Glatzel, Markus

AU - Walkley, Steven U.

AU - Saftig, Paul

AU - Vanier, Marie T.

AU - Braulke, Thomas

PY - 2008/8

Y1 - 2008/8

N2 - The neuronal ceroid lipofuscinoses comprise a group of inherited severe neurodegenerative lysosomal disorders characterized by lysosomal dysfunction and massive accumulation of fluorescent lipopigments and aggregated proteins. To examine the role of lipids in neurodegenerative processes of these diseases, we analysed phospho- and glycolipids in the brains of ctsd-/- and nclf mice, disease models of cathepsin D and CLN6 deficiency, respectively. Both ctsd-/- and nclf mice exhibited increased levels of GM2 and GM3 gangliosides. Immunohistochemically GM2 and GM3 staining was found preferentially in neurons and glial cells, respectively, of ctsd-/- mice. Of particular note, a 20-fold elevation of the unusual lysophospholipid bis(monoacylglycero)phosphate was specifically detected in the brain of ctsd-/- mice accompanied with sporadic accumulation of unesterified cholesterol in distinct cells. The impaired processing of the sphingolipid activator protein precursor, an in vitro cathepsin D substrate, in the brain of ctsd-/- mice may provide the mechanistic link to the storage of lipids. These studies show for the first time that cathepsin D regulates the lysosomal phospho- and glycosphingolipid metabolism suggesting that defects in the composition, trafficking and/or recycling of membrane components along the late endocytic pathway may be critical for the pathogenesis of early onset neuronal ceroid lipofuscinoses.

AB - The neuronal ceroid lipofuscinoses comprise a group of inherited severe neurodegenerative lysosomal disorders characterized by lysosomal dysfunction and massive accumulation of fluorescent lipopigments and aggregated proteins. To examine the role of lipids in neurodegenerative processes of these diseases, we analysed phospho- and glycolipids in the brains of ctsd-/- and nclf mice, disease models of cathepsin D and CLN6 deficiency, respectively. Both ctsd-/- and nclf mice exhibited increased levels of GM2 and GM3 gangliosides. Immunohistochemically GM2 and GM3 staining was found preferentially in neurons and glial cells, respectively, of ctsd-/- mice. Of particular note, a 20-fold elevation of the unusual lysophospholipid bis(monoacylglycero)phosphate was specifically detected in the brain of ctsd-/- mice accompanied with sporadic accumulation of unesterified cholesterol in distinct cells. The impaired processing of the sphingolipid activator protein precursor, an in vitro cathepsin D substrate, in the brain of ctsd-/- mice may provide the mechanistic link to the storage of lipids. These studies show for the first time that cathepsin D regulates the lysosomal phospho- and glycosphingolipid metabolism suggesting that defects in the composition, trafficking and/or recycling of membrane components along the late endocytic pathway may be critical for the pathogenesis of early onset neuronal ceroid lipofuscinoses.

KW - Bis(monoacylglycero)phosphate

KW - Cathepsin D

KW - GM2 ganglioside

KW - Lysosomes

KW - Mouse brain

KW - Neuronal ceroid lipofuscinosis

UR - http://www.scopus.com/inward/record.url?scp=48249146962&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=48249146962&partnerID=8YFLogxK

U2 - 10.1111/j.1471-4159.2008.05497.x

DO - 10.1111/j.1471-4159.2008.05497.x

M3 - Article

C2 - 18498441

AN - SCOPUS:48249146962

VL - 106

SP - 1415

EP - 1425

JO - Journal of Neurochemistry

JF - Journal of Neurochemistry

SN - 0022-3042

IS - 3

ER -