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

Yao, D. et al. (2014) Neuronal expression of galnac transferase is sufficient to prevent the age-related neurodegenerative phenotype of complex ganglioside-deficient mice. Journal of Neuroscience, 34(3), pp. 880-891. (doi:10.1523/JNEUROSCI.3996-13.2014)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Barrie, Mrs Jennifer and Willison, Professor Hugh and Cunningham, Dr Madeleine and McGonigal, Dr Rhona and Edgar, Dr Julia and Yao, Dr Denggao and Meehan, Dr Gavin and Fewou, Dr Simon
Authors: Yao, D., McGonigal, R., Barrie, J. A., Cappell, J., Cunningham, M. E., Meehan, G. R., Fewou, S. N., Edgar, J. M., Rowan, E., Ohmi, Y., Furukawa, K., Furukawa, K., Brophy, P. J., and Willison, H. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Journal of Neuroscience
Publisher:The Society for Neuroscience
ISSN:0270-6474
ISSN (Online):1529-2401
Copyright Holders:Copyright © 2014 The Authors
First Published:First published in Journal of Neuroscience 34(3):880-891
Publisher Policy:Reproduced under a Creative Commons License
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
544031The structural and functional diversity of anti-glycolipid antibody repertoires and their nerve binding domains in human autoimmune neuropathyHugh WillisonWellcome Trust (WELLCOME)092805/Z/10/ZIII -IMMUNOLOGY