The PLP mutants from mouse to man

Abstract

Research on the pathophysiology and possible therapy of Pelizaeus–Merzbacher disease (PMD) has been greatly aided by the availability of a significant number of models known as myelin mutants [1–3]. The majority of the Xlinked myelin mutants has been shown to have mutations in the proteolipid protein (PLP) gene. Like PMD and its allelic disorder, spastic paraplegia type II (SPG-II), the mutants have a variable phenotype ranging from those that die at 21– 25 days of age to those that can live almost indefinitely if hand-reared. The most severely affected mutants include the jimpy (jp) mouse and its alleles jp, jp, and the myelindeficient (md) rat. Moderately affected mutants include the shaking pup (shp) and the paralytic tremor (pt) rabbit, and mildly affected the rumpshaker (jp) mouse [3]. In addition to these naturally occurring models, several rodent models that overexpress or underexpress PLP have been generated. These animals provide ideal tools in which to examine the effects of abnormal or missing PLP on myelin formation and maintenance. The degree of severity of the phenotype correlates well with the severity of myelination defects. That is, early death at 3–4 weeks of age is reflected by an almost total absence of myelin in the central nervous system (CNS), such as in the jp mouse and md rat. In contrast, mutants that live longer, such as the shp and pt rabbits, have much more myelin yet substantially less than in wild type. Other features of the pathology of the mutants are particularly relevant to understanding how PLP deficiency affects myelination. In the severely affected mutants, a notable apoptotic death of oligodendrocytes is seen [4]. Whether this is the primary defect that causes disruption of myelination has been debated. Interestingly, it has been shown that in the most mildly affected mutant jp, cell death is not a feature [5]. Ultrastructural analyses have identified two important features of the mutants. First, disruption of PLP production results in a failure of