Processing of PLP in a model of Pelizaeus-Merzbacher disease/SPG2 due to the rumpshaker mutation

Glia
Mark McLaughlinIan R Griffiths

Abstract

The rumpshaker mutation of the X-linked myelin proteolipid protein (PLP1) gene causes spastic paraplegia type 2 or a mild form of Pelizaeus-Merzbacher disease in man. The identical mutation occurs spontaneously in mice. Both human and murine diseases are associated with dysmyelination. Using the mouse model, we show that the low steady state levels of PLP result from accelerated proteasomal degradation rather than decreased synthesis. The T(1/2) for degradation of rumpshaker PLP is 11 h compared with 23 h for wild type. A minority of newly synthesized PLP is incorporated into myelin in the correct orientation but at a reduced rate compared with wild type. However, inhibition of proteasomal degradation does not increase the level of PLP incorporated into myelin. As Plp null mice do not have a similar myelin deficiency, it is unlikely that the reduced PLP levels are the main cause of the dysmyelination. Rumpshaker oligodendrocytes also have a reduced level of other myelin proteins, such as MBP, although the mechanisms are not yet defined but are likely to operate at a translational or post-translational level.

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Citations

May 20, 2008·Expert Reviews in Molecular Medicine·Karen J Woodward
Jul 31, 2007·Expert Opinion on Pharmacotherapy·Stephan Züchner
Jan 21, 2016·Developmental Medicine and Child Neurology·Catherine SarretOdile Boespflug-Tanguy
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Nov 25, 2016·Stem Cells·M Joana OsorioSteven A Goldman
Jan 20, 2017·Frontiers in Molecular Neuroscience·Vera G VolpiMaurizio D'Antonio

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