Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 101, Issue 27, Pages 10132-10136Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0401900101
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Funding
- NHLBI NIH HHS [HL56370, HL69799, HL66157, R01 HL056370, HL60546, P50 HL052318, HL52318, R01 HL066157] Funding Source: Medline
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An R120G missense mutation in the small heat shock protein alpha-B-crystallin (CryAB(R120G)) 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 CryAB(R120G) 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 CryAB(R120G) establish the necessity and sufficiency of CryAB(R120G) 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.
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