Abstract
Progranulin (GRN) loss-of-function mutations leading to progranulin protein (PGRN) haploinsufficiency are prevalent genetic causes of frontotemporal dementia. Reports also indicated PGRN-mediated neuroprotection in models of Alzheimer's and Parkinson's disease; thus, increasing PGRN levels is a promising therapeutic for multiple disorders. To uncover novel PGRN regulators, we linked whole-genome sequence data from 920 individuals with plasma PGRN levels and identified the prosaposin (PSAP) locus as a new locus significantly associated with plasma PGRN levels. Here we show that both PSAP reduction and overexpression lead to significantly elevated extracellular PGRN levels. Intriguingly, PSAP knockdown increases PGRN monomers, whereas PSAP overexpression increases PGRN oligomers, partly through a protein–protein interaction. PSAP-induced changes in PGRN levels and oligomerization replicate in human-derived fibroblasts obtained from a GRN mutation carrier, further supporting PSAP as a potential PGRN-related therapeutic target. Future studies should focus on addressing the relevance and cellular mechanism by which PGRN oligomeric species provide neuroprotection.
Highlights
Progranulin (GRN) loss-of-function mutations leading to progranulin protein (PGRN) haploinsufficiency are prevalent genetic causes of frontotemporal dementia
To identify genetic loci that regulate plasma PGRN levels in non-demented individuals, we conducted a genome-wide association study (GWAS) using whole-genome sequencing (WGS) data obtained for 920 individuals from 20 Mexican-American families for which plasma PGRN levels were measured by an enzyme-linked immunosorbent assay (ELISA)
The single nucleotide polymorphisms (SNPs) most strongly associated with plasma PGRN levels was rs646776 located near the PGRN receptor SORT1 on chromosome 1, replicating our earlier findings which were based on a smaller GWAS using roughly 300,000 SNPs
Summary
Progranulin (GRN) loss-of-function mutations leading to progranulin protein (PGRN) haploinsufficiency are prevalent genetic causes of frontotemporal dementia. Reports indicated PGRN-mediated neuroprotection in models of Alzheimer’s and Parkinson’s disease; increasing PGRN levels is a promising therapeutic for multiple disorders. In 2006, loss-of-function mutations in the PGRN gene (GRN) were identified as a common cause of the neurodegenerative disorder frontotemporal dementia (FTD)[15,16]. A common GRN variant, possibly leading to a partial reduction in PGRN levels, has further been suggested as a genetic risk factor for FTD and related neurodegenerative disorders, emphasizing the important role of PGRN in the development of multiple diseases[22,23,24,25,26,27]. No PGRN-modifying therapies are currently available to patients with neurodegenerative disorders
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