Transmissible spongiform encephalopathy in the gray tremor mutant mouse.

Abstract

Gray tremor (gt) is an autosomal recessive mutation in the mouse linked to caracul (Ca) on chromosome 15. The complex mutant phenotype includes pigmentation defects, tremor, seizures, hypo-and dysmyelination in central and peripheral nervous systems, spongiform encephalopathy, and early death. The heterozygote (+/gt) is phenotypically normal but develops a mild spongiform encephalopathy from 2 months of age onward. The pigmentation and myelination disorders indicate that the gt genetic locus is active neonatally and probably earlier. This report focuses mainly on the later-expressed vacuolating disorder, which most closely mimics in tissue distribution, histopathology, and ultrastructure the spongiform encephalopathies caused by unconventional transmissible agents. This lesion was produced in genetically normal mice in a transmission experiment: of 99 neonatal mice inoculated intracerebrally with gt/gt brain homogenate, all 7 mice of three strains (BALB/cBy, C3HeB/FeJ, and C57BL/6J) allowed to survive for the unusually long interval of 682-721 days after inoculation, developed spongiform changes distributed as in the mutant phenotype. The gray tremor mutant presents a naturally occurring spongiform encephalopathy whose expression is determined by the interaction of genetic factors and a transmissible agent.

Scrapie Agent Proteins Do Not Accumulate in Grey Tremor Mice

“…Scrapie is transmissible in its entirety: host animals develop the characteristic clinical syndrome and neuropathology. Previous work on the GT mutant demonstrated that the pathological changes characteristic of the homozygote could be transmitted to genotypically normal mice after an incubation period as long as 2 years (Sidman et al, 1985). Mice inoculated with gt/gt brain homogenates did not develop a clinical syndrome resembling that of either the gt/gt homozygote or scrapie (Sidman et al, 1985;Hoffman et al, 1987).…”

“…Mice homozygous for the grey tremor (GT) trait (gt/gt) display a characteristic pigmentation of their coats, seizures, tremors, ataxia and death by 90 days of age (Sidman et al, 1985). The neuropathology is a non-inflammatory spongiform appearance to the brain (Kinney & Sidman, 1986) resembling that of the transmissible spongiform diseases scrapie and Creutzfeldt-Jakob disease (CJD).…”

“…The neuropathology is a non-inflammatory spongiform appearance to the brain (Kinney & Sidman, 1986) resembling that of the transmissible spongiform diseases scrapie and Creutzfeldt-Jakob disease (CJD). The spongiform neuropathology, but not the neurological syndrome characteristic of the homozygote gt/gt, was transmitted to genetically normal mice by inoculation with gt/gt brain homogenates (Sidman et al, 1985). In a second report on transmission of GT disease, NFS/N mice were inoculated with gt/gt brain homogenate (Hoffman et al, 1987).…”

“…These proteins have apparent Mrs of 28K to 31K, 23K to 26K and 21K and are similar to those • +, Present; -, absent. ~" The gt mutation has been linked to the caracul locus on chromosome 15 (Sidman et al, 1985). The gene(s) for scrapie incubation period control and encoding Cp33-37 and Sp33 37 are on chromosome 2(Sparkesetal., 1986;Carlson et aL, 1986).…”

“…We searched for scrapie agent-specific proteins in GT mouse brain to investigate further the suggestion by Sidman et al (1985) that the scrapie agent might be involved in the transmission of the spongiform encephalopathy characteristic of this mutant.…”