title: Ndrg1 in development and maintenance of the myelin sheath.
abstract: CMT4D disease is a severe autosomal recessive demyelinating neuropathy with extensive axonal loss leading to early disability, caused by mutations in the N-myc downstream regulated gene 1 (NDRG1). NDRG1 is expressed at particularly high levels in the Schwann cell (SC), but its physiological function(s) are unknown. To help with their understanding, we characterise the phenotype of a new mouse model, stretcher (str), with total Ndrg1 deficiency, in comparison with the hypomorphic Ndrg1 knock-out (KO) mouse. While both models display normal initial myelination and a transition to overt pathology between weeks 3 and 5, the markedly more severe str phenotype suggests that even low Ndrg1 expression results in significant phenotype rescue. Neither model replicates fully the features of CMT4D: although axon damage is present, regenerative capacity is unimpaired and the mice do not display the early severe axonal loss typical of the human disease. The widespread large fibre demyelination coincides precisely with the period of rapid growth of the animals and the dramatic (160-500-fold) increase in myelin volume and length in large fibres. This is followed by stabilisation after week 10, while small fibres remain unaffected. Gene expression profiling of str peripheral nerve reveals non-specific secondary changes at weeks 5 and 10 and preliminary data point to normal proteasomal function. Our findings do not support the proposed roles of NDRG1 in growth arrest, terminal differentiation, gene expression regulation and proteasomal degradation. Impaired SC trafficking failing to meet the considerable demands of nerve growth, emerges as the likely pathogenetic mechanism in NDRG1 deficiency.
authors.affiliation: Department of Clinical Neurosciences, Institute of Neurology, UCL, London NW3 2PF, UK. r.king@medsch.ucl.ac.uk
authors.forename: Rosalind H M
authors.initials: RH
authors.lastname: King
authors.forename: David
authors.initials: D
authors.lastname: Chandler
authors.forename: Sash
authors.initials: S
authors.lastname: Lopaticki
authors.forename: Dexing
authors.initials: D
authors.lastname: Huang
authors.forename: Julian
authors.initials: J
authors.lastname: Blake
authors.forename: John R
authors.initials: JR
authors.lastname: Muddle
authors.forename: Trevor
authors.initials: T
authors.lastname: Kilpatrick
authors.forename: Michelle
authors.initials: M
authors.lastname: Nourallah
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Miyata
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Okuda
authors.forename: Kim W
authors.initials: KW
authors.lastname: Carter
authors.forename: Michael
authors.initials: M
authors.lastname: Hunter
authors.forename: Dora
authors.initials: D
authors.lastname: Angelicheva
authors.forename: Grant
authors.initials: G
authors.lastname: Morahan
authors.forename: Luba
authors.initials: L
authors.lastname: Kalaydjieva
mesh_terms: D000818:Animals; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003711:Demyelinating Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004594:Electrophysiology; D015870:Gene Expression; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012035:Refsum Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012583:Schwann Cells / Q000378:metabolism* / Q000473:pathology; D012584:Sciatic Nerve / Q000378:metabolism / Q000473:pathology; D000099259:N-myc Downstream-Regulated Gene 1 Protein
chemical_list: D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D000099259:N-myc Downstream-Regulated Gene 1 Protein