Primary myopathy and accumulation of PRPSc-like molecules in peripheral tissues of transgenic mice expressing a prion protein insertional mutation

R. Chiesa, A. Pestronk, R. E. Schmidt, W. G. Tourtellotte, Bernardino Ghetti, P. Piccardo, D. A. Harris

Research output: Contribution to journalArticle

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Abstract

A nine-octapeptide insertional mutation in the prion protein (PrP) gene is associated with an inherited variant of Creutzfeldt-Jakob disease in humans. Transgenic mice that express the mouse PrP homologue of this mutation (designated PG14) under control of a PrP promoter display a progressive neurological disorder characterized by ataxia, apoptosis of cerebellar granule cells, and accumulation in the brain of mutant PrP molecules that display the biochemical hallmarks of PrPSc, the pathogenic isoform of PrP. In this report, we have investigated the expression of PG14 PrP in the peripheral tissues of these mice. We found highest levels of mutant PrP in the brain and spinal cord, intermediate levels in skeletal muscle, heart, and testis and low levels in kidney, lung, spleen, intestine, and stomach. Up to 70% of the PG14 PrP expressed in peripheral tissues was detergent-insoluble, and digestion with low concentrations of proteinase K yielded a PrP 27-30 fragment. These results suggest that the mutant protein was converted to a physical state reminiscent of PrPSc, although its infectivity remains to be determined. Histological analysis of skeletal muscle, one of the peripheral tissues with the highest level of PG14 PrP, revealed features indicative of a progressive, primary myopathy, including central nuclei, necrotic and regenerating fibers, and variable fiber size. These results indicate that the PG14 mutation structurally alters the protein in a way that promotes conversion to a PrPSc-like state, regardless of the tissue context, and suggest that accumulation of PrPSc can have deleterious effects on skeletal muscle cells as well as on neurons.

Original languageEnglish
Pages (from-to)279-288
Number of pages10
JournalNeurobiology of Disease
Volume8
Issue number2
DOIs
StatePublished - 2001

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Muscular Diseases
Transgenic Mice
Mutation
Mutant Proteins
Skeletal Muscle
Prion Proteins
Endopeptidase K
Cerebellar Ataxia
Creutzfeldt-Jakob Syndrome
Brain
Nervous System Diseases
Detergents
Muscle Cells
Intestines
Testis
Digestion
Spinal Cord
Stomach
Protein Isoforms
Spleen

ASJC Scopus subject areas

  • Neurology

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Primary myopathy and accumulation of PRPSc-like molecules in peripheral tissues of transgenic mice expressing a prion protein insertional mutation. / Chiesa, R.; Pestronk, A.; Schmidt, R. E.; Tourtellotte, W. G.; Ghetti, Bernardino; Piccardo, P.; Harris, D. A.

In: Neurobiology of Disease, Vol. 8, No. 2, 2001, p. 279-288.

Research output: Contribution to journalArticle

Chiesa, R. ; Pestronk, A. ; Schmidt, R. E. ; Tourtellotte, W. G. ; Ghetti, Bernardino ; Piccardo, P. ; Harris, D. A. / Primary myopathy and accumulation of PRPSc-like molecules in peripheral tissues of transgenic mice expressing a prion protein insertional mutation. In: Neurobiology of Disease. 2001 ; Vol. 8, No. 2. pp. 279-288.
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