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Assembly of CNS myelin in the absence of proteolipid protein
M Klugmann1, M H Schwab, A Pühlhofer
1Zentrum für Molekulare Biologie (ZMBH) University of Heidelburg, Federal Republic of Germany.
Abstract:
Two proteolipid proteins, PLP and DM20, are the major membrane components of central nervous system (CNS) myelin. Mutations of the X-linked PLP/DM20 gene cause dysmyelination in mouse and man and result in significant mortality. Here we show that mutant mice that lack expression of a targeted PLP gene fail to exhibit the known dysmyelinated phenotype. Unable to encode PLP/DM20 or PLP-related polypeptides, oligodendrocytes are still competent to myelinate CNS axons of all calibers and to assemble compacted myelin sheaths. Ultrastructurally, however, the electron-dense 'intraperiod' lines in myelin remain condensed, correlating with its reduced physical stability. This suggests that after myelin compaction, PLP forms a stabilizing membrane junction, similar to a "zipper." Dysmyelination and oligodendrocyte death emerge as an epiphenomenon of other PLP mutations and have been uncoupled in the PLP null allele from the risk of premature myelin breakdown.
Insights
Central nervous system (CNS) myelin relies on proteolipid proteins (PLP) and DM20. PLP null mice myelinate axons without PLP, revealing its role in myelin stability, not initial formation.
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Proteolipid proteins (PLP) and DM20 are key components of CNS myelin.
- Mutations in the PLP/DM20 gene cause severe dysmyelination and mortality in mice and humans.
Purpose of the Study:
- To investigate the specific role of PLP in CNS myelin formation and stability.
- To determine if PLP is essential for oligodendrocyte function and myelin compaction.
Main Methods:
- Generation and analysis of PLP null mutant mice lacking PLP gene expression.
- Ultrastructural examination of CNS myelin in mutant mice.
- Assessment of oligodendrocyte competence in myelination.
Main Results:
- PLP null mice successfully myelinate CNS axons despite lacking PLP/DM20 expression.
- Myelin sheaths in PLP null mice are compacted but exhibit reduced physical stability.
- The electron-dense intraperiod lines of myelin are condensed, suggesting PLP's role in stabilizing compacted myelin.
Conclusions:
- PLP is not essential for initial CNS myelin formation or compaction.
- PLP functions as a stabilizing junction, akin to a zipper, in already compacted myelin.
- Dysmyelination and oligodendrocyte death observed in other PLP mutations are likely secondary effects, uncoupled from myelin breakdown in PLP null mice.