MRPL3 is one of the proteins essential in the mitochondrial ribosome and the spontaneous mutation decrepit (Mrpl3dcr) is an approximately 133 bp insertion containing an extensive T repeat inserted into the intron between exons 6 and 7. While Mrpl3 homozygous null mutations cause embryonic lethality by E9.5, the decrepit mutation is a hypomorph that causes adult onset neurodegeneration. Increased citrate synthase activity was found in mitochondria extracted from brains of adult decrepit homozygotes and assessment via the Barnes maze revealed impaired learning and progressive loss of spatial memory. Homozygotes develop progressive bilateral focal ischemia in the brain beginning by 12 weeks of age, when an eosin-pale, sharply bounded region is found in the cortex of most homozygotes. This expands by 14 weeks with all homozygotes showing the phenotype, by 16 weeks the inferior hippocampus and other areas are also affected, and by 18 weeks those homozygotes that survive have large regions of vacuolated tissue in the inferior cortex and hippocampus, and the dorsal cortex is also affected. T2-weighted MRI revealed hyperintensities indicative of cell death in the piriform and entorhinal cortices at 70 days, the limbic area, cingulate cortex, striatum, and nucleus accumbens at 86 days, the motor cortex and hippocampus at 96 days, and the substantia nigra at 125 days, which is consistent with the initial histological findings. The volume of several brain structures differs significantly from normal, either larger or smaller depending on the structure, between 50 and 150 days of age. As a result of this underlying pathology, homozygotes develop an unkempt scruffy coat and hunched posture by approximately 10 weeks of age and are over-excited by stimulation. Wasting begins around 12 weeks of age, lethargy by approximately 15 weeks, and death generally occurs between 18 and 22 weeks, but can be earlier or later. Histological assessment found pathology restricted to the brain. The brain vacuoles show bilateral symmetry, and no hemorrhage or emboli are found, suggesting these vacuoles do not result from strokes. X-ray micro-CT found an increase in the number of primarily small vessel segments in the cerebrovasculature after 100 days of age when neurodegeneration has already occurred. (Sproule et al., 2010; Cahill et al., 2020.)

The spontaneous mutation decrepit (Mrpl3dcr) provides a model of early-adult onset limbic neurodegeneration.

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