Ndrg1 in development and maintenance of the myelin sheath

R.H.M. King, David Chandler, S. Lopaticki, D. Huang, J. Blake, J.R. Muddle, T. Kilpatrick, M. Nourallah, T. Miyata, T. Okuda, Kim Carter, Michael Hunter, Dora Angelicheva, Grant Morahan, Luba Kalaydjieva

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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.
Original languageEnglish
Pages (from-to)368-380
Number of pages13
JournalNeurobiology of Disease
Volume42
Issue number3
Early online date6 Feb 2011
DOIs
Publication statusPublished - Jun 2011

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Stretchers
Myelin Sheath
Maintenance
Schwann Cells
Phenotype
Genes
Growth
Gene Expression Regulation
Gene Expression Profiling
Demyelinating Diseases
Peripheral Nerves
Knockout Mice
Axons
Pathology
Mutation
Hereditary motor and sensory neuropathy, LOM type

Cite this

King, R. H. M., Chandler, D., Lopaticki, S., Huang, D., Blake, J., Muddle, J. R., ... Kalaydjieva, L. (2011). Ndrg1 in development and maintenance of the myelin sheath. Neurobiology of Disease, 42(3), 368-380. https://doi.org/10.1016/j.nbd.2011.01.030
King, R.H.M. ; Chandler, David ; Lopaticki, S. ; Huang, D. ; Blake, J. ; Muddle, J.R. ; Kilpatrick, T. ; Nourallah, M. ; Miyata, T. ; Okuda, T. ; Carter, Kim ; Hunter, Michael ; Angelicheva, Dora ; Morahan, Grant ; Kalaydjieva, Luba. / Ndrg1 in development and maintenance of the myelin sheath. In: Neurobiology of Disease. 2011 ; Vol. 42, No. 3. pp. 368-380.
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King, RHM, Chandler, D, Lopaticki, S, Huang, D, Blake, J, Muddle, JR, Kilpatrick, T, Nourallah, M, Miyata, T, Okuda, T, Carter, K, Hunter, M, Angelicheva, D, Morahan, G & Kalaydjieva, L 2011, 'Ndrg1 in development and maintenance of the myelin sheath' Neurobiology of Disease, vol. 42, no. 3, pp. 368-380. https://doi.org/10.1016/j.nbd.2011.01.030

Ndrg1 in development and maintenance of the myelin sheath. / King, R.H.M.; Chandler, David; Lopaticki, S.; Huang, D.; Blake, J.; Muddle, J.R.; Kilpatrick, T.; Nourallah, M.; Miyata, T.; Okuda, T.; Carter, Kim; Hunter, Michael; Angelicheva, Dora; Morahan, Grant; Kalaydjieva, Luba.

In: Neurobiology of Disease, Vol. 42, No. 3, 06.2011, p. 368-380.

Research output: Contribution to journalArticle

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T1 - Ndrg1 in development and maintenance of the myelin sheath

AU - King, R.H.M.

AU - Chandler, David

AU - Lopaticki, S.

AU - Huang, D.

AU - Blake, J.

AU - Muddle, J.R.

AU - Kilpatrick, T.

AU - Nourallah, M.

AU - Miyata, T.

AU - Okuda, T.

AU - Carter, Kim

AU - Hunter, Michael

AU - Angelicheva, Dora

AU - Morahan, Grant

AU - Kalaydjieva, Luba

PY - 2011/6

Y1 - 2011/6

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AB - 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.

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JO - Neurobiology of Disease

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King RHM, Chandler D, Lopaticki S, Huang D, Blake J, Muddle JR et al. Ndrg1 in development and maintenance of the myelin sheath. Neurobiology of Disease. 2011 Jun;42(3):368-380. https://doi.org/10.1016/j.nbd.2011.01.030