Evidence that CNS Hypomyelination Does Not Cause Death of Jimpy-msd Mutant Mice

Abstract

Mice expressing three of the proteolipid protein (Plp) mutations in the mouse (jimpy, jimpy-msd, and jimpy-4J) all have a severe deficiency of CNS myelin and oligodendrocytes (OLs), and die sometime in their 4th postnatal week. The prevailing view has been that the animals’ shortened life span and lack of myelin are causally related. Here we describe the survival of jimpy-msd males for as long as postnatal day (P) 210. Although these spontaneously occurring longer-lived jimpy-msd males show a 2- to 8-fold increase in numbers of myelinated axons in many CNS regions, this does not protect them from a later but still premature death. Investigating the cause of premature death may reveal previously undiscovered properties of the myelin genes or the cells that express them, or perhaps additional unsuspected cellular responses that contribute to the disease. This study identifies small accumulations of inflammatory cells in the brain parenchyma of jimpy-msd mice as young as P14 and as old as P60, suggesting that the pathology of the disease produced by at least this Plp mutation may be far more complex than has been previously recognized.

Clinically relevant intronic splicing enhancer mutation in myelin proteolipid protein leads to progressive microglia and astrocyte activation in white and gray matter regions of the brain

“…Our findings of robust microglia activation in the CNS in both white and gray matter regions of the PLP-ISEdel mice add to the growing body of literature which suggests that disruptions in PLP protein promote microglia activation [15-24] (see Table 3). In agreement with our findings, a similar pattern of microglia activation to the PLP-ISEdel mice has been reported in PLP1 transgenic mouse (PLP1tg) [16,19].…”

“…Focusing on regional heterogeneity of white matter, recent work has shown that alterations in myelin proteins including proteolipid protein (PLP) and 2′,3′-cyclic-nucleotide 3′-phosphodiesterase (CNP) alone can induce a robust microglia response [15-29]. PLP is the most abundant protein of myelin in the CNS.…”

Genetic background determines phenotypic severity of the Plp rumpshaker mutation

“…The shiverer mouse, an Mbp deletion mutant, contains less myelin than the C57 rumpshaker , yet lives 2.5 to 3 times as long. Furthermore, long‐lived myelin mutants with virtually no myelin have been described (Duncan et al, 1995; Billings‐Gagliardi et al, 1999; Wolf et al, 1999). Therefore, there seems no direct correlation between the amount of myelin and the longevity of mutant mice.…”

Quaking*Shiverer Double-Mutant Mice Survive for at Least 100 Days with No CNS Myelin

“…Another answer is the presence of abnormal myelin and functionally compromised OLs. A third answer is suggested by signs of an inflammatory reaction that we have reported in the companion paper [1]. Perhaps an inflammatory reaction, provoked by certain kinds of abnormal myelin, somehow incites fatal convulsions that are the proximate cause of death.…”

“…However, we have now shown that there is no direct relationship between the short life span of mice expressing juvenile-lethal proteolipid protein (Plp) gene mutations and their lack of myelin. Increasing amounts of mutant myelin in the CNS of longer-lived males expressing myelin synthesis deficiency (Plp jp-msd ; here abbreviated jp-msd) does not protect them from a later but still premature death [1]. It could be argued that this is an anomalous result that reflects some unique peculiarity of the jp-msd mutation.…”