Desmin-related cardiomyopathy in transgenic mice: A cardiac amyloidosis

Atsushi Sanbe, Hanna Osinska, Jeffrey E. Saffitz, Charles G. Glabe, Rakez Kayed, Alina Maloyan, Jeffrey Robbins

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Abstract

An R120G missense mutation in the small heat shock protein α-B-crystallin (CryABR120G) causes desmin-related cardiomyopathy (DRM). DRM is characterized by the formation of aggregates containing CryAB and desmin, and it can be recapitulated in transgenic mice by cardiac-specific expression of the mutant protein. In this article, we show that expression of CryABR120G leads to the formation of electron-dense bodies characteristic of the DRMs and identify these bodies as aggresomes, which are characteristic of the neurodegenerative diseases. Cardiomyocytes transfected with adenovirus containing CryABR120G establish the necessity and sufficiency of CryABR120G expression for aggresome formation. The commonality of these aggresomes with oligomeric protein aggregates found in the amyloid-related degenerative diseases was corroborated by the presence of high levels of amyloid oligomers that may represent a primary toxic species in the amyloid diseases. These oligomeric amyloid intermediates are present also in cardiomyocytes derived from many human dilated and hypertrophic cardiomyopathies.

Original languageEnglish (US)
Pages (from-to)10132-10136
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number27
DOIs
StatePublished - Jul 6 2004

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