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Pathogenic cysteine mutations affect progranulin function and production of mature granulins

2009; Wiley; Volume: 112; Issue: 5 Linguagem: Inglês

10.1111/j.1471-4159.2009.06546.x

1471-4159

Jun Wang, Philip Van Damme, Carlos Cruchaga, Michael A. Gitcho, José Vidal, Manuel Seijo‐Martínez, Lei Wang, Jane Y. Wu, Wim Robberecht, Alison Goate,

Alzheimer's disease research and treatments

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.