title: Secretory leukocyte protease inhibitor protein regulates the penetrance of frontotemporal lobar degeneration in progranulin mutation carriers.
abstract: 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.
authors.affiliation: Proteomics Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Ghidoni
authors.forename: Rosa
authors.initials: R
authors.lastname: Flocco
authors.forename: Anna
authors.initials: A
authors.lastname: Paterlini
authors.forename: Michela
authors.initials: M
authors.lastname: Glionna
authors.forename: Loredana
authors.initials: L
authors.lastname: Caruana
authors.forename: Elisa
authors.initials: E
authors.lastname: Tonoli
authors.forename: Giuliano
authors.initials: G
authors.lastname: Binetti
authors.forename: Luisa
authors.initials: L
authors.lastname: Benussi
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000097:blood* / Q000235:genetics* / Q000401:mortality; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D007558:Italy; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D000077153:Progranulins; D012044:Regression Analysis; D053481:Secretory Leukocyte Peptidase Inhibitor / Q000097:blood*
chemical_list: C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D053481:Secretory Leukocyte Peptidase Inhibitor
keywords: Frontotemporal dementia; GRN; Kaplan-Meier Survival curves; SLPI protein; mutation; pedigrees; plasma; progranulin