Uncoupling of hypomyelination and glial cell death by a mutation in the proteolipid protein gene.
Proteolipid protein (PLP; M(r) 30,000) is a highly conserved major polytopic membrane protein in myelin but its cellular function remains obscure. Neurological mutant mice can often provide model systems for human genetic disorders. Mutations of the X-chromosome-linked PLP gene are lethal, identified first in the jimpy mouse and subsequently in patients with Pelizaeus-Merzbacher disease. The unexplained phenotype of these mutations includes degeneration and premature cell death of oligodendrocytes with associated hypomyelination. Here we show that a new mouse mutant rumpshaker is defined by the amino-acid substitution Ile-to-Thr at residue 186 in a membrane-embedded domain of PLP. Surprisingly, rumpshaker mice, although myelin-deficient, have normal longevity and a full complement of morphologically normal oligodendrocytes. Hypomyelination can thus be genetically separated from the PLP-dependent oligodendrocyte degeneration. We suggest that PLP has a vital function in glial cell development, distinct from its later role in myelin assembly, and that this dichotomy of action may explain the clinical spectrum of Pelizaeus-Merzbacher disease.
Schneider
A
A
Zentrum für Molekulare Biologie (ZMBH), Universität Heidelberg, Germany.
Montague
P
P
Griffiths
I
I
Fanarraga
M
M
Kennedy
P
P
Brophy
P
P
Nave
K A
KA
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D016923:Cell Death; D003711:Demyelinating Diseases / Q000235:genetics* / Q000473:pathology; D002549:Diffuse Cerebral Sclerosis of Schilder / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008818:Mice, Neurologic Mutants / Q000033:anatomy & histology / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D009185:Myelin Proteins / Q000235:genetics*; D018991:Myelin Proteolipid Protein; D009457:Neuroglia / Q000473:pathology*; D013329:Structure-Activity Relationship
D008565:Membrane Proteins; D009185:Myelin Proteins; D018991:Myelin Proteolipid Protein