Secretory leukocyte protease inhibitor protein regulates the penetrance of frontotemporal lobar degeneration in progranulin mutation carriers

The discovery that mutations in the gene encoding for progranulin (GRN) cause frontotemporal lobar degeneration (FTLD) and other neurodegenerative diseases leading to dementia has brought renewed interest in progranulin and its functions in the central nervous system. Full length progranulin is pres...

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Published inJournal of Alzheimer's disease Vol. 38; no. 3; p. 533
Main Authors Ghidoni, Roberta, Flocco, Rosa, Paterlini, Anna, Glionna, Michela, Caruana, Loredana, Tonoli, Elisa, Binetti, Giuliano, Benussi, Luisa
Format Journal Article
LanguageEnglish
Published Netherlands 01.01.2014
Subjects
Adult
Age Factors
Aged
Female
Frontotemporal Lobar Degeneration - blood
Frontotemporal Lobar Degeneration - genetics
Frontotemporal Lobar Degeneration - mortality
Humans
Intercellular Signaling Peptides and Proteins - genetics
Italy
Kaplan-Meier Estimate
Male
Middle Aged
Mutation - genetics
Pedigree
Regression Analysis
Secretory Leukocyte Peptidase Inhibitor - blood
Italy
mutation
GRN
progranulin
Kaplan-Meier Survival curves
SLPI protein
pedigrees
Frontotemporal dementia
plasma
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Summary:The discovery that mutations in the gene encoding for progranulin (GRN) cause frontotemporal lobar degeneration (FTLD) and other neurodegenerative diseases leading to dementia has brought renewed interest in progranulin and its functions in the central nervous system. Full length progranulin is preserved from cleavage by secretory leukocyte protease inhibitor (SLPI), one of the smallest serine protease inhibitor circulating in plasma. Herein, we investigated the relationship between circulating SLPI and progranulin in affected and unaffected subjects belonging to 26 Italian pedigrees carrying GRN null mutations. In GRN null mutation carriers, we demonstrated: i) an increase of circulating SLPI levels in affected subjects; ii) an age-related upregulation of the serine-protease inhibitor in response to lifetime progranulin shortage; and iii) a delay in the age of onset in subjects with the highest SLPI protein levels. The study of SLPI and its relation to progranulin suggests the existence of unexpected molecular players in progranulin-associated neurodegeneration.
ISSN:1875-8908
DOI:10.3233/JAD-131163