NR ANZZ
AU Bosque,P.J.; Telling,G.C.; Westaway,D.; Cayetano-Canlas,J.; DeArmond,S.J.; Prusiner,S.B.
TI Prion protein overexpression exclusively in skeletal-muscle causes spontaneous myopathy
QU Neurology 1996; 46(N2): S73.006
PT Meeting Abstract
VT
S73. 006
4:45 PM
Objective. To determine whether the myopathy seen in transgenic (Tg) mice overexpressing the prion protein (PrP) is due to overexpression of PrP in muscle.
Background. Tg mice, which express PrP at high levels under control of a PrP gene promoter, develop hind limb paralysis and histologic evidence of a myopathy at ages ranging from 220 to 733 days. This myopathy has been attributed to overexpression of PrP within the muscle, although PrP is expressed in these mice at a level at least tenfold higher in the CNS than in muscle.
Design/Methods. To study PrP expression exclusively in skeletal muscle, we established lines of Tg mice expressing hybrid gene constructs. One consisted of the muscle creatine kinase promoter/enhancer of ~3 kb stimulating expression of Syrian hamster (SHa) PrP. A second was composed of a chicken a-actin promoter of 218 bp driving expression of mouse PrP gene. We determined transgene levels by dot hybridization, protein expression by Western blot, and muscle histology by light microscopy.
Results. Line D8775 expresses SHsprP in skeletal muscle at a level about four times that in SHa brain, at a lower level in heart, and at almost undetectable levels in other organs. To date, 2 of 3 mice 285 days of age, and 1 of 6 mice 253 days of age have developed reduced spontaneous movement, difficulty righting, and an axial tremor. The ill mice show a myopathy marked by central nuclei, variable fiber size, ragged-red fibers, and endomysial fibrosis. Three Tg mice expressing mouse PrP only in skeletal muscle, at a level about equal to that of SHaPrP in the mice described above, do not yet show signs of myopathy at 336 days of age.
Conclusion. These studies argue that the myopathy previously seen in older Tg(SHaprP) mice is due to SHaprP expression in muscle. SHaPrP may be more toxic to mouse muscle than is mouse PrP.
ZR 0 Zitate
SP englisch
OR Prion-Krankheiten 2