Affiliations: [a] Proteomics Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy | [b] NeuroBioGen Lab-Memory Clinic, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
Correspondence:
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Correspondence to: Dr. Roberta Ghidoni, Proteomics Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, via Pilastroni 4, 25125 Brescia, Italy. Tel.: +39 030 3501725; Fax: +39 030 3501592; E-mail: rghidoni@fatebenefratelli.it.
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.
