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Title: Pathogenic cysteine mutations affect progranulin function and production of mature granulins
Authors: Wang, Jun ×
Van Damme, Philip
Cruchaga, Carlos
Gitcho, Michael A
Vidal, Jose Manuel
Seijo-Martínez, Manuel
Wang, Lei
Wu, Jane Y
Robberecht, Wim
Goate, Alison #
Issue Date: Mar-2010
Publisher: Raven Press
Series Title: Journal of Neurochemistry vol:112 issue:5 pages:1305-1315
Abstract: Frontotemporal dementia with ubiquitin-positive inclusions (FTLD-U) can be caused by mutations in the progranulin gene (GRN). Progranulin (PGRN) is a cysteine-rich growth factor, which is proteolytically cleaved by elastase to produce several granulins (GRNs). All FTLD-U mutations in GRN characterized to date result in reduced secreted PGRN protein. We recently reported a Spanish family with progressive non-fluent aphasia and dementia in which a novel C521Y mutation segregates with disease. A second cysteine mutation (C139R) has also been reported to be disease specific. Allele-specific mRNA expression assays in brain reveal that the C521Y mutant allele is expressed at similar levels to the wild-type allele. Furthermore, plasma PGRN levels in C521Y carriers are comparable with non-carrier family relatives, suggesting that the mutation does not affect PGRN protein expression and secretion in vivo. Despite normal PGRN levels C521Y and C139R mutant GRNs show reduced neurite growth-stimulating activity in vitro. Further study revealed that these mutations also cause impaired cleavage of PGRN by elastase. Our data suggest that these mutations affect the function of full-length PGRN as well as elastase cleavage of PGRN into GRNs, leading to neurodegeneration.
URI: 
ISSN: 0022-3042
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Research Group Experimental Neurology
Laboratory for Neurobiology (Vesalius Research Center)
× corresponding author
# (joint) last author

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