Neuronal expression of GalNAc transferase is sufficient to prevent the age-related neurodegenerative phenotype of complex ganglioside-deficient mice

Denggao Yao, Rhona McGonigal, Jennifer A. Barrie, Joanna Cappell, Madeleine E. Cunningham, Gavin R. Meehan, Simon N. Fewou, Julia M. Edgar, Edward Rowan, Yuhsuke Ohmi, Keiko Furukawa, Koichi Furukawa, Peter J. Brophy, Hugh J. Willison

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Gangliosides are widely expressed sialylated glycosphingolipids with multifunctional properties in different cell types and organs. In the nervous system, they are highly enriched in both glial and neuronal membranes. Mice lacking complex gangliosides attributable to targeted ablation of the B4galnt1 gene that encodes β-1,4-N-acetylegalactosaminyltransferase 1 (GalNAc–transferase; GalNAcT−/−) develop normally before exhibiting an age-dependent neurodegenerative phenotype characterized by marked behavioral abnormalities, central and peripheral axonal degeneration, reduced myelin volume, and loss of axo-glial junction integrity. The cell biological substrates underlying this neurodegeneration and the relative contribution of either glial or neuronal gangliosides to the process are unknown. To address this, we generated neuron-specific and glial-specific GalNAcT rescue mice crossed on the global GalNAcT−/− background [GalNAcT−/−-Tg(neuronal) and GalNAcT−/−-Tg(glial)] and analyzed their behavioral, morphological, and electrophysiological phenotype. Complex gangliosides, as assessed by thin-layer chromatography, mass spectrometry, GalNAcT enzyme activity, and anti-ganglioside antibody (AgAb) immunohistology, were restored in both neuronal and glial GalNAcT rescue mice. Behaviorally, GalNAcT−/−-Tg(neuronal) retained a normal “wild-type” (WT) phenotype throughout life, whereas GalNAcT−/−-Tg(glial) resembled GalNAcT−/− mice, exhibiting progressive tremor, weakness, and ataxia with aging. Quantitative electron microscopy demonstrated that GalNAcT−/− and GalNAcT−/−-Tg(glial) nerves had significantly increased rates of axon degeneration and reduced myelin volume, whereas GalNAcT−/−-Tg(neuronal) and WT appeared normal. The increased invasion of the paranode with juxtaparanodal Kv1.1, characteristically seen in GalNAcT−/− and attributed to a breakdown of the axo-glial junction, was normalized in GalNAcT−/−-Tg(neuronal) but remained present in GalNAcT−/−-Tg(glial) mice. These results indicate that neuronal rather than glial gangliosides are critical to the age-related maintenance of nervous system integrity.
LanguageEnglish
Pages880-891
Number of pages12
JournalJournal of Neuroscience
Volume34
Issue number3
DOIs
Publication statusPublished - 15 Jan 2014

Fingerprint

Gangliosides
Neuroglia
Phenotype
Myelin Sheath
Nervous System
polypeptide N-acetylgalactosaminyltransferase
Glycosphingolipids
Tremor
Ataxia
Thin Layer Chromatography
Axons
Anti-Idiotypic Antibodies
Mass Spectrometry
Electron Microscopy
Maintenance
Neurons

Keywords

  • ganglioside
  • glycosyltransferase
  • neurodegeneration
  • transgenic

Cite this

Yao, Denggao ; McGonigal, Rhona ; Barrie, Jennifer A. ; Cappell, Joanna ; Cunningham, Madeleine E. ; Meehan, Gavin R. ; Fewou, Simon N. ; Edgar, Julia M. ; Rowan, Edward ; Ohmi, Yuhsuke ; Furukawa, Keiko ; Furukawa, Koichi ; Brophy, Peter J. ; Willison, Hugh J. / Neuronal expression of GalNAc transferase is sufficient to prevent the age-related neurodegenerative phenotype of complex ganglioside-deficient mice. In: Journal of Neuroscience. 2014 ; Vol. 34, No. 3. pp. 880-891.
@article{2a47ee5a7b8b4c15bff3595b0be1c86a,
title = "Neuronal expression of GalNAc transferase is sufficient to prevent the age-related neurodegenerative phenotype of complex ganglioside-deficient mice",
abstract = "Gangliosides are widely expressed sialylated glycosphingolipids with multifunctional properties in different cell types and organs. In the nervous system, they are highly enriched in both glial and neuronal membranes. Mice lacking complex gangliosides attributable to targeted ablation of the B4galnt1 gene that encodes β-1,4-N-acetylegalactosaminyltransferase 1 (GalNAc–transferase; GalNAcT−/−) develop normally before exhibiting an age-dependent neurodegenerative phenotype characterized by marked behavioral abnormalities, central and peripheral axonal degeneration, reduced myelin volume, and loss of axo-glial junction integrity. The cell biological substrates underlying this neurodegeneration and the relative contribution of either glial or neuronal gangliosides to the process are unknown. To address this, we generated neuron-specific and glial-specific GalNAcT rescue mice crossed on the global GalNAcT−/− background [GalNAcT−/−-Tg(neuronal) and GalNAcT−/−-Tg(glial)] and analyzed their behavioral, morphological, and electrophysiological phenotype. Complex gangliosides, as assessed by thin-layer chromatography, mass spectrometry, GalNAcT enzyme activity, and anti-ganglioside antibody (AgAb) immunohistology, were restored in both neuronal and glial GalNAcT rescue mice. Behaviorally, GalNAcT−/−-Tg(neuronal) retained a normal “wild-type” (WT) phenotype throughout life, whereas GalNAcT−/−-Tg(glial) resembled GalNAcT−/− mice, exhibiting progressive tremor, weakness, and ataxia with aging. Quantitative electron microscopy demonstrated that GalNAcT−/− and GalNAcT−/−-Tg(glial) nerves had significantly increased rates of axon degeneration and reduced myelin volume, whereas GalNAcT−/−-Tg(neuronal) and WT appeared normal. The increased invasion of the paranode with juxtaparanodal Kv1.1, characteristically seen in GalNAcT−/− and attributed to a breakdown of the axo-glial junction, was normalized in GalNAcT−/−-Tg(neuronal) but remained present in GalNAcT−/−-Tg(glial) mice. These results indicate that neuronal rather than glial gangliosides are critical to the age-related maintenance of nervous system integrity.",
keywords = "ganglioside, glycosyltransferase, neurodegeneration, transgenic",
author = "Denggao Yao and Rhona McGonigal and Barrie, {Jennifer A.} and Joanna Cappell and Cunningham, {Madeleine E.} and Meehan, {Gavin R.} and Fewou, {Simon N.} and Edgar, {Julia M.} and Edward Rowan and Yuhsuke Ohmi and Keiko Furukawa and Koichi Furukawa and Brophy, {Peter J.} and Willison, {Hugh J.}",
year = "2014",
month = "1",
day = "15",
doi = "10.1523/JNEUROSCI.3996-13.2014",
language = "English",
volume = "34",
pages = "880--891",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "3",

}

Yao, D, McGonigal, R, Barrie, JA, Cappell, J, Cunningham, ME, Meehan, GR, Fewou, SN, Edgar, JM, Rowan, E, Ohmi, Y, Furukawa, K, Furukawa, K, Brophy, PJ & Willison, HJ 2014, 'Neuronal expression of GalNAc transferase is sufficient to prevent the age-related neurodegenerative phenotype of complex ganglioside-deficient mice' Journal of Neuroscience, vol. 34, no. 3, pp. 880-891. https://doi.org/10.1523/JNEUROSCI.3996-13.2014

Neuronal expression of GalNAc transferase is sufficient to prevent the age-related neurodegenerative phenotype of complex ganglioside-deficient mice. / Yao, Denggao; McGonigal, Rhona; Barrie, Jennifer A.; Cappell, Joanna; Cunningham, Madeleine E.; Meehan, Gavin R.; Fewou, Simon N.; Edgar, Julia M. ; Rowan, Edward; Ohmi, Yuhsuke ; Furukawa, Keiko; Furukawa, Koichi; Brophy, Peter J.; Willison, Hugh J.

In: Journal of Neuroscience, Vol. 34, No. 3, 15.01.2014, p. 880-891.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Neuronal expression of GalNAc transferase is sufficient to prevent the age-related neurodegenerative phenotype of complex ganglioside-deficient mice

AU - Yao, Denggao

AU - McGonigal, Rhona

AU - Barrie, Jennifer A.

AU - Cappell, Joanna

AU - Cunningham, Madeleine E.

AU - Meehan, Gavin R.

AU - Fewou, Simon N.

AU - Edgar, Julia M.

AU - Rowan, Edward

AU - Ohmi, Yuhsuke

AU - Furukawa, Keiko

AU - Furukawa, Koichi

AU - Brophy, Peter J.

AU - Willison, Hugh J.

PY - 2014/1/15

Y1 - 2014/1/15

N2 - Gangliosides are widely expressed sialylated glycosphingolipids with multifunctional properties in different cell types and organs. In the nervous system, they are highly enriched in both glial and neuronal membranes. Mice lacking complex gangliosides attributable to targeted ablation of the B4galnt1 gene that encodes β-1,4-N-acetylegalactosaminyltransferase 1 (GalNAc–transferase; GalNAcT−/−) develop normally before exhibiting an age-dependent neurodegenerative phenotype characterized by marked behavioral abnormalities, central and peripheral axonal degeneration, reduced myelin volume, and loss of axo-glial junction integrity. The cell biological substrates underlying this neurodegeneration and the relative contribution of either glial or neuronal gangliosides to the process are unknown. To address this, we generated neuron-specific and glial-specific GalNAcT rescue mice crossed on the global GalNAcT−/− background [GalNAcT−/−-Tg(neuronal) and GalNAcT−/−-Tg(glial)] and analyzed their behavioral, morphological, and electrophysiological phenotype. Complex gangliosides, as assessed by thin-layer chromatography, mass spectrometry, GalNAcT enzyme activity, and anti-ganglioside antibody (AgAb) immunohistology, were restored in both neuronal and glial GalNAcT rescue mice. Behaviorally, GalNAcT−/−-Tg(neuronal) retained a normal “wild-type” (WT) phenotype throughout life, whereas GalNAcT−/−-Tg(glial) resembled GalNAcT−/− mice, exhibiting progressive tremor, weakness, and ataxia with aging. Quantitative electron microscopy demonstrated that GalNAcT−/− and GalNAcT−/−-Tg(glial) nerves had significantly increased rates of axon degeneration and reduced myelin volume, whereas GalNAcT−/−-Tg(neuronal) and WT appeared normal. The increased invasion of the paranode with juxtaparanodal Kv1.1, characteristically seen in GalNAcT−/− and attributed to a breakdown of the axo-glial junction, was normalized in GalNAcT−/−-Tg(neuronal) but remained present in GalNAcT−/−-Tg(glial) mice. These results indicate that neuronal rather than glial gangliosides are critical to the age-related maintenance of nervous system integrity.

AB - Gangliosides are widely expressed sialylated glycosphingolipids with multifunctional properties in different cell types and organs. In the nervous system, they are highly enriched in both glial and neuronal membranes. Mice lacking complex gangliosides attributable to targeted ablation of the B4galnt1 gene that encodes β-1,4-N-acetylegalactosaminyltransferase 1 (GalNAc–transferase; GalNAcT−/−) develop normally before exhibiting an age-dependent neurodegenerative phenotype characterized by marked behavioral abnormalities, central and peripheral axonal degeneration, reduced myelin volume, and loss of axo-glial junction integrity. The cell biological substrates underlying this neurodegeneration and the relative contribution of either glial or neuronal gangliosides to the process are unknown. To address this, we generated neuron-specific and glial-specific GalNAcT rescue mice crossed on the global GalNAcT−/− background [GalNAcT−/−-Tg(neuronal) and GalNAcT−/−-Tg(glial)] and analyzed their behavioral, morphological, and electrophysiological phenotype. Complex gangliosides, as assessed by thin-layer chromatography, mass spectrometry, GalNAcT enzyme activity, and anti-ganglioside antibody (AgAb) immunohistology, were restored in both neuronal and glial GalNAcT rescue mice. Behaviorally, GalNAcT−/−-Tg(neuronal) retained a normal “wild-type” (WT) phenotype throughout life, whereas GalNAcT−/−-Tg(glial) resembled GalNAcT−/− mice, exhibiting progressive tremor, weakness, and ataxia with aging. Quantitative electron microscopy demonstrated that GalNAcT−/− and GalNAcT−/−-Tg(glial) nerves had significantly increased rates of axon degeneration and reduced myelin volume, whereas GalNAcT−/−-Tg(neuronal) and WT appeared normal. The increased invasion of the paranode with juxtaparanodal Kv1.1, characteristically seen in GalNAcT−/− and attributed to a breakdown of the axo-glial junction, was normalized in GalNAcT−/−-Tg(neuronal) but remained present in GalNAcT−/−-Tg(glial) mice. These results indicate that neuronal rather than glial gangliosides are critical to the age-related maintenance of nervous system integrity.

KW - ganglioside

KW - glycosyltransferase

KW - neurodegeneration

KW - transgenic

U2 - 10.1523/JNEUROSCI.3996-13.2014

DO - 10.1523/JNEUROSCI.3996-13.2014

M3 - Article

VL - 34

SP - 880

EP - 891

JO - Journal of Neuroscience

T2 - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 3

ER -