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Processing of PLP in a model of Pelizaeus‐Merzbacher disease/SPG2 due to the rumpshaker mutation
Author(s) -
McLaughlin Mark,
Barrie Jennifer A.,
Karim Saadia,
Montague Paul,
Edgar Julia M.,
Kirkham Douglas,
Thomson Christine E.,
Griffiths Ian R
Publication year - 2006
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.20325
Subject(s) - biology , mutation , genetics , gene
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. © 2006 Wiley‐Liss, Inc.