Progranulin as a Potential Biomarker of Central Nervous System Disease

Abstract

Progranulin is a cysteine-rich secreted protein initially identified as a growth factor. Progranulin has been implicated in multiple biological and pathological processes, including tumorigenesis, inflammation, neurodegeneration and lysosomal function. Loss of one allele of the progranulin gene (GRN) leads to frontotemporal lobar degeneration (FTLD). GRN null mutations cause haploinsufficiency, leading to a significant decrease in progranulin protein levels in the plasma, serum and cerebrospinal fluid (CSF) of carriers. Recently, several reports have shown that plasma progranulin levels predict GRN mutation status in patients with FTLD and asymptomatic family members. Thus, the concentration of circulating progranulin is a useful biomarker for screening GRN mutation carriers. Interestingly, there are also conditions in which expression of progranulin is increased. For example, progranulin is highly overexpressed in aggressive cancer cell lines and tissue specimens from various malignancies. Furthermore, progranulin expression in tumor and serum samples correlates with pathological grading and prognosis in several types of cancer. In the central nervous system (CNS), progranulin is often highly expressed in gliomas. Recently, we reported increased progranulin levels in the CSF of patients with CNS lymphomas and carcinomas with CNS metastasis. Accordingly, CSF progranulin levels may be useful as a diagnostic and monitoring marker for CNS metastases of lymphomas and carcinomas. Progranulin is also associated with various autoimmune diseases. For example, in rheumatoid arthritis and systemic lupus erythematosus, progranulin serum levels positively correlate with disease activity. Several reports also suggest an association with autoimmune CNS diseases, including multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). Increased CSF progranulin levels are observed in the acute phase of these diseases. Additionally, although still controversial, increased progranulin levels appear to be associated with remission of symptoms in MS and NMOSD. Therefore, progranulin may be a promising therapeutic agent and useful biomarker of CNS diseases, including GRN-related neurodegenerative diseases, malignancies, and autoimmune neurological disorders.