title: Secretion of amyloidogenic gelsolin progressively compromises protein homeostasis leading to the intracellular aggregation of proteins.
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.
authors: Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Lesley J
authors: LJ
authors: Page
authors: Ji Young
authors: JY
authors: Suk
authors: Lyudmila
authors: L
authors: Bazhenova
authors: Sheila M
authors: SM
authors: Fleming
authors: Malcolm
authors: M
authors: Wood
authors: Yun
authors: Y
authors: Jiang
authors: Ling T
authors: LT
authors: Guo
authors: Andrew P
authors: AP
authors: Mizisin
authors: Robert
authors: R
authors: Kisilevsky
authors: G Diane
authors: GD
authors: Shelton
authors: William E
authors: WE
authors: Balch
authors: Jeffery W
authors: JW
authors: Kelly
mesh_terms: D000682:Amyloid / Q000378:metabolism*; D028226:Amyloidosis, Familial / Q000473:pathology; D000818:Animals; D002196:Capillaries / Q000473:pathology; D018260:Gelsolin / Q000378:metabolism*; D006706:Homeostasis; D006720:Homozygote; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018485:Muscle Fibers, Skeletal / Q000473:pathology / Q000648:ultrastructure; D009124:Muscle Proteins / Q000737:chemistry / Q000378:metabolism; D018908:Muscle Weakness / Q000378:metabolism / Q000473:pathology; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D018979:Myositis, Inclusion Body / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism; D010641:Phenotype; D020836:Protein Structure, Quaternary; D014617:Vacuoles / Q000648:ultrastructure
chemical_list: D000682:Amyloid; D018260:Gelsolin; D009124:Muscle Proteins; D050505:Mutant Proteins; D010446:Peptide Fragments