title: Subtle gait abnormalities in Nedd4 heterozygous mice.
abstract: Nedd4 is a widely expressed ubiquitin ligase that is necessary for normal neuronal development and function. However, largely due to the lethality of Nedd4 homozygous knockout mice, little is known about the physiological roles of Nedd4 in the adult brain. In this study we used Nedd4 heterozygous mice, which are viable and live to maturity, to assess for motor function and gait. Global motor function was not altered in these mice, a result consistent with the low level of Nedd4 expression observed in motor neurons of the spinal cord. However, Nedd4 heterozygous mice showed significant age-dependent changes in gait. The gait abnormalities included an overall extension of gait that was only evident in the 6 month old mice. We also observed distinct expression patterns of Nedd4, with pronounced staining in the Purkinje neurons of the cerebellum that are crucial for normal gait, and lower levels in other motor areas of the CNS. It has been recently shown that Nedd4 directly interacts with GluR1 containing AMPA receptors in an activity dependent manner to modulate receptor levels at the post-synaptic membrane. Using confocal immunohistochemistry, we found that there were subtle changes in GluR1 expression in 6 month old Nedd4 heterozygous mice. There appeared to be a redistribution of GluR1 into larger puncta in the molecular layer and in the membrane of the soma of the Purkinje neurons. This study is the first to show that a 50% reduction in Nedd4 levels is sufficient to produce significant gait defects in 6 month old mice. These defects may arise in part, from altered distribution of GluR1 in cerebellar neurons.
authors.affiliation: Health Innovations Research Institute, School of Medical Science, RMIT University, PO Box 71, Bundoora, VIC 3083, Australia.
authors.forename: Daria
authors.initials: D
authors.lastname: Camera
authors.affiliation: Centre for Cancer Biology, SA Pathology, Frome Road, Adelaide, SA 5000, Australia.
authors.forename: Natasha A
authors.initials: NA
authors.lastname: Boase
authors.affiliation: Centre for Cancer Biology, SA Pathology, Frome Road, Adelaide, SA 5000, Australia; Department of Medicine, University of Adelaide, North Terrace, Adelaide, SA 5000, Australia; Division of Health Science, University of South Australia, North Terrace, Adelaide, SA 5000, Australia.
authors.forename: Sharad
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Health Innovations Research Institute, School of Medical Science, RMIT University, PO Box 71, Bundoora, VIC 3083, Australia.
authors.forename: David V
authors.initials: DV
authors.lastname: Pow
authors.affiliation: Health Innovations Research Institute, School of Medical Science, RMIT University, PO Box 71, Bundoora, VIC 3083, Australia; School of Medical Sciences and The Bosch Institute, The University of Sydney, Camperdown, NSW 2006, Australia. Electronic address: philip.poronnik@sydney.edu.au.
authors.forename: Philip
authors.initials: P
authors.lastname: Poronnik
mesh_terms: D000367:Age Factors; D000818:Animals; D015153:Blotting, Western; D001835:Body Weight; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism*; D005684:Gait / Q000502:physiology; D020233:Gait Disorders, Neurologic / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006579:Heterozygote; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D000075702:Nedd4 Ubiquitin Protein Ligases; D009929:Organ Size; D011689:Purkinje Cells / Q000378:metabolism; D018091:Receptors, AMPA / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D000075702:Nedd4 Ubiquitin Protein Ligases; D018091:Receptors, AMPA; D044767:Ubiquitin-Protein Ligases; C000618461:Nedd4l protein, mouse
keywords: AMPAR; Cerebellum; E3 ubiquitin ligase; Gait; GluR1