Secretion of amyloidogenic gelsolin progressively compromises protein homeostasis leading to the intracellular aggregation of proteins
Open Access
- 7 July 2009
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 106 (27), 11125-11130
- https://doi.org/10.1073/pnas.0811753106
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.Keywords
This publication has 35 references indexed in Scilit:
- Biological and Chemical Approaches to Diseases of Proteostasis DeficiencyAnnual Review of Biochemistry, 2009
- Chemical and Biological Approaches Synergize to Ameliorate Protein-Folding DiseasesCell, 2008
- From endoplasmic-reticulum stress to the inflammatory responseNature, 2008
- Interrelation of inflammation and APP in sIBM: IL-1β induces accumulation of β-amyloid in skeletal muscleBrain, 2008
- Physical basis of colors seen in Congo red-stained amyloid in polarized lightLaboratory Investigation, 2008
- The Parkinson's disease protein α-synuclein disrupts cellular Rab homeostasisProceedings of the National Academy of Sciences, 2008
- Peripheral Transgene Expression of Plasma Gelsolin Reduces Amyloid in Transgenic Mouse Models of Alzheimer's DiseaseMolecular Therapy, 2007
- Pathogenic accumulation of APP in fast twitch muscle of IBM patients and a transgenic modelNeurobiology of Aging, 2006
- Recombinant plasma gelsolin infusion attenuates burn-induced pulmonary microvascular dysfunctionJournal of Applied Physiology, 2004
- Toward understanding the pathogenic mechanisms in gelsolin-related amyloidosis: in vitro expression reveals an abnormal gelsolin fragmentHuman Molecular Genetics, 1994