Progranulin: at the interface of neurodegenerative and metabolic diseases

Abstract

Progranulin is a widely expressed, cysteine-rich, secreted glycoprotein originally discovered for its growth factor-like properties. Its subsequent identification as a causative gene for frontotemporal dementia (FTD), a devastating early-onset neurodegenerative disease, has catalyzed a surge of new discoveries about progranulin function in the brain. More recently, progranulin was recognized as an adipokine involved in diet-induced obesity and insulin resistance, revealing its metabolic function. We review here progranulin biology in both neurodegenerative and metabolic diseases. In particular, we highlight the growth factor-like, trophic, and anti-inflammatory properties of progranulin as potential unifying themes in these seemingly divergent conditions. We also discuss potential therapeutic options for raising progranulin levels to treat progranulin-deficient FTD, as well as the possible consequences of such treatment.

Figure 1. Genetic deficiency of progranulin influences neurological and metabolic diseases

Decreased progranulin levels cause neurodegenerative disease and exacerbate atherosclerosis, yet protect against some aspects of metabolic disease. Patients with loss of function mutations in one progranulin allele develop frontotemporal dementia, while loss of both progranulin alleles leads to neuronal ceroid lipofuscinosis. Further, reduced progranulin levels may also be a risk factor for Alzheimer disease. Conversely, deletion of progranulin in normal mice protects against diet-induced obesity. However, loss of progranulin in mice that lack apo-E promotes the development of atherosclerosis. Thus, loss of progranulin is apparently disease-causing in the brain and has mixed effects on metabolic disease in the periphery. Dysregulation of progranulin-mediated cell growth and inflammation may be involved in the pathogenesis of both subsets of disease.

Figure I. (for Box 1). Overview of progranulin biochemistry

Progranulin is composed of 7.5 highly homologous, cysteine-rich repeats called granulins, shown in blue, that are separated by linker regions, shown in white, which share less sequence homology. A signal sequence, shown in red, is required for secretion. Progranulin can be cleaved into granulins by proteases, including neutrophil elastase, proteinase 3, MMP-12, ADAMTS-7, and possibly others. Cleavage can be prevented by binding to the protease inhibitor secretory leukocyte protease inhibitor (SLPI). Progranulin’s reported cell-surface receptors include sortilin and TNF receptors. The binding of progranulin to TNFRs is controversial (see text). Granulin receptors are unknown.