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.
authors.affiliation: Institute of Infection, Immunity, and Inflammation, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8TA, United Kingdom, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0NR, United Kingdom, Department of Biochemistry II, Nagoya University School of Medicine, Nagoya 466-0065, Japan, and Centre for Neuroregeneration, University of Edinburgh, Edinburgh EH16 4SB, United Kingdom.
authors.forename: Denggao
authors.initials: D
authors.lastname: Yao
authors.forename: Rhona
authors.initials: R
authors.lastname: McGonigal
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Barrie
authors.forename: Joanna
authors.initials: J
authors.lastname: Cappell
authors.forename: Madeleine E
authors.initials: ME
authors.lastname: Cunningham
authors.forename: Gavin R
authors.initials: GR
authors.lastname: Meehan
authors.forename: Simon N
authors.initials: SN
authors.lastname: Fewou
authors.forename: Julia M
authors.initials: JM
authors.lastname: Edgar
authors.forename: Edward
authors.initials: E
authors.lastname: Rowan
authors.forename: Yuhsuke
authors.initials: Y
authors.lastname: Ohmi
authors.forename: Keiko
authors.initials: K
authors.lastname: Furukawa
authors.forename: Koichi
authors.initials: K
authors.lastname: Furukawa
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Brophy
authors.forename: Hugh J
authors.initials: HJ
authors.lastname: Willison
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D005732:Gangliosides / Q000172:deficiency* / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017350:N-Acetylgalactosaminyltransferases / Q000096:biosynthesis / Q000235:genetics*; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D000097763:Polypeptide N-acetylgalactosaminyltransferase
chemical_list: D005732:Gangliosides; D017350:N-Acetylgalactosaminyltransferases; D000097763:Polypeptide N-acetylgalactosaminyltransferase
keywords: ganglioside; glycosyltransferase; neurodegeneration; transgenic