Secretion of amyloidogenic gelsolin progressively compromises protein homeostasis leading to the intracellular aggregation of proteins.
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.
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Lesley J
LJ
Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Suk
Ji Young
JY
Bazhenova
Lyudmila
L
Fleming
Sheila M
SM
Wood
Malcolm
M
Jiang
Yun
Y
Guo
Ling T
LT
Mizisin
Andrew P
AP
Kisilevsky
Robert
R
Shelton
G Diane
GD
Balch
William E
WE
Kelly
Jeffery W
JW
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
D000682:Amyloid; D018260:Gelsolin; D009124:Muscle Proteins; D050505:Mutant Proteins; D010446:Peptide Fragments