Human Molecular Genetics, 2003, Vol. 12, No. 13 1609-1620
DOI: 10.1093/hmg/ddg173
© 2003 Oxford University Press
Distinct chaperone mechanisms can delay the formation of aggresomes by the myopathy-causing R120G 
B-crystallin mutant
Centre de recherche en cancérologie de l'Université Laval, L'Hôtel-Dieu de Québec, 9 rue McMahon, Québec, Canada G1R 2J6
Received March 10, 2003; Revised April 30, 2003; Accepted May 7, 2003
A familial form of desmin-related myopathy (DRM) is associated with a missense mutation (R120G) in 
B-crystallin (B) and is characterized by intracellular desmin aggregation. Because B is a molecular chaperone that participates in the assembly of desmin filaments, it has been suggested that the desmin aggregation might be due to the loss of B function. We report here that BR120G has indeed impaired in vivo function and structure as reflected by a highly reduced capacity to protect cells against heat shock and by an abnormal supramolecular organization even in cells not expressing desmin. In many cells, BR120G accumulated in inclusion bodies that had characteristics of aggresomes concentrating around the centrosome following a microtubule-facilitated process. Three distinct chaperone mechanisms could reduce or even prevent the formation of the BR120G aggresomes. Wild-type B and Hsp27 prevented aggresome formation by co-oligomerizing with BR120G. Hsp70 with its co-chaperone Hdj-1 or Chip-1 but not a mutant of Chip-1 lacking ubiquitin ligase activity, reduced the frequency of aggresome formation likely by targeting BR120G for degradation. Finally, HspB8 interacted only transiently with B but nonetheless rescued the BR120G oligomeric organization, suggesting that it acted as a true chaperone assisting in the folding of the mutant protein. Hence, the formation of inclusion bodies in BR120G-mediated DRM is probably due to the misfolding of BR120G per se and can be delayed or prevented by expression of the wild type B allele or other molecular chaperones, thereby explaining the adult onset of the disease.
* To whom correspondence should be addressed. Tel: +1 4186915281; Fax: +1 4186915439; Email: jacques.landry{at}med.ulaval.ca
Present address: Universidad Centroccidental Lisandro Alvarado, Decanato de Medicina, Departamento de Morfología, Sección de Anatomía Microscópica, Av. Libertador con Av. Andrés Bello, Barquisimeto, Estado Lara, Venezuela.
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