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Evidence that CNS hypomyelination does not cause death of jimpy-msd mutant mice
S Billings-Gagliardi1, J N Nunnari, N L Nadon
1Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA. Susan.Gagliardi@umassmed.edu
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.
Insights
Longer-lived jimpy-msd mice show increased myelinated axons but still die prematurely. This study reveals early brain inflammation, suggesting complex pathology in proteolipid protein (Plp) mutations.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Proteolipid protein (Plp) mutations in mice, such as jimpy, jimpy-msd, and jimpy-4J, cause severe central nervous system (CNS) myelin and oligodendrocyte deficiencies, leading to premature death.
- The established view links the shortened lifespan and myelin deficits in these mouse models directly.
Purpose of the Study:
- To investigate the pathology and survival characteristics of jimpy-msd mice.
- To explore potential underlying causes for premature mortality beyond myelin deficiency.
Main Methods:
- Extended observation of jimpy-msd male mice survival.
- Histological analysis of CNS tissue to assess myelinated axons and cellular infiltrates.
- Comparative analysis of wild-type and mutant mouse brains at various postnatal ages.
Main Results:
- Jimpy-msd male mice survived significantly longer, up to postnatal day 210.
- Increased numbers of myelinated axons were observed in various CNS regions of longer-lived jimpy-msd mice.
- Small inflammatory cell accumulations were detected in the brain parenchyma of jimpy-msd mice from postnatal day 14 to 60.
Conclusions:
- The pathology associated with the jimpy-msd Plp mutation is more complex than previously understood.
- Early-onset inflammation in the CNS may contribute to the premature death observed in these mouse models.
- Further research into myelin gene function and cellular responses is warranted.
