Progranulin: an emerging target for FTLD therapies

Abstract

Frontotemporal lobar degeneration (FTLD), a neurodegenerative disease primarily affecting the frontal and temporal lobes, is one of the most common types of dementia. While the majority of FTLD cases are sporadic, approximately 10-40% of patients have an inherited form of FTLD. Mutations in the progranulin gene (GRN) have recently been identified as a major cause of FTLD with ubiquitin positive inclusions (FTLD-U). Because over 70 disease-linked GRN mutations cause abnormal deficiencies in the production of PGRN, a protein that plays a crucial role in embryogenesis, cell growth and survival, wound repair and inflammation, researchers now aim to design therapies that would increase PGRN levels in affected individuals, thereby alleviating the symptoms associated with disease. Several compounds and genetic factors, as well as PGRN receptors, have recently been identified because of their ability to regulate PGRN levels. Strict quality control measures are needed given that extreme PGRN levels at either end of the spectrum - too low or too high - can lead to neurodegeneration or cancer, respectively. The aim of this review is to highlight what is known regarding PGRN biology; to improve understanding of the mechanisms involved in regulating PGRN levels and highlight studies that are laying the groundwork for the development of effective therapeutic modulators of PGRN. This article is part of a Special Issue entitled RNA-Binding Proteins.

Figure 1

Seventy pathogenic GRN mutations have been identified in over 230 families. In the schematic diagram, mutations are numbered relative to the largest GRN transcript (GenBank accession number NM_002087.2). The gene encodes for a 593 amino acid protein composed of intra-linked granulin peptides that are cleaved by proteases into individual granulins. Secretory leukocyte protease inhibitor (SLPI) protects full-length PGRN by binding to both PGRN and elastase, therefore preventing cleavage into the 6 kDa granulin repeats.

Figure 2

A. The C-terminal end of PGRN binds to the Beta-propeller region of SORT1. Upon binding, uptake of PGRN via SORT1 traffics PGRN to the lysosome. Endocytosed SORT1 is then recycled back to the cell membrane. B. PGRN binding to TNFR acts as an antagonist of TNFα. TNFα binding to TNFR activates pro-inflammatory signaling to induce inflammation. PGRN blocks this signaling pathway when bound to TNFR therefore inhibiting inflammation.