Secretion of amyloidogenic gelsolin progressively compromises protein homeostasis leading to the intracellular aggregation of proteins

doi:10.1073/pnas.0811753106

Secretion of amyloidogenic gelsolin progressively compromises protein homeostasis leading to the intracellular aggregation of proteins

Department of ^aCell Biology,
^bDepartments of Chemistry and Molecular and Experimental Medicine,
^fDepartment of Chemical Physiology, and
^gInstitute for Childhood and Neglected Diseases, and
^hThe Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037;
^cDepartment of Neurobiology, The David Geffen School of Medicine, University of California, Los Angeles, CA 90095;
^dDepartment of Pathology, University of California at San Diego, La Jolla, CA 92093; and
^eDepartments of Pathology and Molecular Medicine, and Biochemistry, Queen's University, Kingston, ON, Canada K7L 3N6

Edited by Charles Weissmann, Scripps Florida, Jupiter, FL, and approved May 1, 2009
↵¹J.Y.S. and L.B. contributed equally to this work. (received for review November 20, 2008)

Abstract

Familial amyloidosis of Finnish type (FAF) is a systemic amyloid disease associated with the deposition of proteolytic fragments of mutant (D187N/Y) plasma gelsolin. We report a mouse model of FAF featuring a muscle-specific promoter to drive D187N gelsolin synthesis. This model recapitulates the aberrant endoproteolytic cascade and the aging-associated extracellular amyloid deposition of FAF. Amyloidogenesis is observed only in tissues synthesizing human D187N gelsolin, despite the presence of full-length D187N gelsolin and its 68-kDa cleavage product in blood—demonstrating the importance of local synthesis in FAF. Loss of muscle strength was progressive in homozygous D187N gelsolin mice. The presence of misfolding-prone D187N gelsolin appears to exacerbate the age-associated decline in cellular protein homeostasis (proteostasis), reflected by the intracellular deposition of numerous proteins, a characteristic of the most common degenerative muscle disease of aging humans, sporadic inclusion body myositis.

Footnotes

²To whom correspondence may be addressed. E-mail: webalch{at}scripps.edu or jkelly{at}scripps.edu
Author contributions: L.J.P., W.E.B., and J.W.K. designed research; L.J.P., J.Y.S., L.B., Y.J., L.T.G., and A.P.M. performed research; L.J.P., S.M.F., M.W., Y.J., L.T.G., A.P.M., R.K., G.D.S., and W.E.B. analyzed data; L.J.P., G.D.S., W.E.B., and J.W.K. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0811753106/DCSupplemental.