Progranulin axis and recent developments in frontotemporal lobar degeneration

Abstract

Frontotemporal lobar degeneration (FTLD) is a devastating neurodegenerative disease that is the second most common form of dementia affecting individuals under age 65. The most common pathological subtype, FTLD with transactive response DNA-binding protein with a molecular weight of 43 kDa inclusions (FTLD-TDP), is often caused by autosomal dominant mutations in the progranulin gene (GRN) encoding the progranulin protein (PGRN). GRN pathogenic mutations result in haploinsufficiency, usually by nonsense-mediated decay of the mRNA. Since the discovery of these mutations in 2006, several groups have published data and animal models that provide further insight into the genetic and functional relevance of PGRN in the context of FTLD-TDP. These studies were critical in initiating our understanding of the role of PGRN in neural development, degeneration, synaptic transmission, cell signaling, and behavior. Furthermore, recent publications have now identified the receptors for PGRN, which will hopefully lead to additional therapeutic targets. Additionally, drug screens have been conducted to identify pharmacological regulators of PGRN levels to be used as potential treatments for PGRN haploinsufficiency. Here we review recent literature describing relevant data on GRN genetics, cell culture experiments describing the potential role and regulators of PGRN in the central nervous system, animal models of PGRN deficiency, and potential PGRN-related FTLD therapies that are currently underway. The present review aims to underscore the necessity of further elucidation of PGRN biology in FTLD-related neurodegeneration.

Figure 1

Overview of pathogenic loss-of-function mutations and potential pathogenic missense progranulin mutations in frontotemporal lobar degeneration. Mutations in the progranulin gene (GRN) are a common cause of frontotemporal lobar degeneration with transactivation response DNA binding protein molecular weight of 43 kDa pathology (FTLD-TDP). Schematic representation of the genomic structure of GRN (top) and progranulin protein (PGRN) (bottom). The gray numbered boxes in the genomic structure indicate the noncoding exon 1 and the 3' untranslated region; the green numbered boxes indicate coding exons 2 to 13. The white lettered boxes in PGRN refer to the individual granulin domains. A total of 70 different loss-of-function mutations scattered over all GRN exons, except exon 13, have been reported. These mutations are indicated with vertical brown lines on the GRN exons and listed above the exons with their cDNA numbering relative to the largest GRN transcript (GenBank accession number NM_002087.2). Four potential pathogenic missense mutations are indicated in red with their protein numbering according to the largest PGRN isoform GenPept accession number NP_002078.1).