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, B. Ghetti, P. Piccardo, D. A. Harris

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

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 (US)
Article number90400
Pages (from-to)279-288
Number of pages10
JournalNeurobiology of Disease
Volume8
Issue number2
DOIs
StatePublished - 2001

Funding

We thank Richard Kascsak for supplying 3F4 antibody and Cheryl Adles for maintaining the mouse colony. We also acknowledge Jeffrey Saffitz, Mary Zutter, and Helen Liapis for help in histological analysis of mouse tissues, Jeffrey Miner for advice on evaluation of renal function, and Attila Kovacs for performing echocardiography. This work was supported by grants to D.A.H. from the American Health Assistance Foundation and the Alzheimer’s Association, to R.E.S. from the NIH (R01 AG10299 and R37 DK19645), to W.G.T. from the HHMI and the NIH (MH0 1426), and to B.G. from the NIH (R01 NS14426 and P30 AG10133). R.C. was the recipient of fellowships from the Comitato Telethon Fondazione Onlus and the McDonnell Center for Cellular and Molecular Neurobiology at Washington University.

ASJC Scopus subject areas

  • Neurology

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