Prosaposin is a regulator of progranulin levels and oligomerization

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.

Impaired prosaposin lysosomal trafficking in frontotemporal lobar degeneration due to progranulin mutations

“…Consistent with our study, PSAP was shown to regulate plasma PGRN levels in humans33. Thus, by forming a complex, PSAP and PGRN facilitate each other's lysosomal trafficking.…”

The interaction between progranulin and prosaposin is mediated by granulins and the linker region between saposin B and C

“…In fibroblasts which do not express sortilin, PGRN lysosomal trafficking is totally dependent on PSAP (Zhou et al 2015). The interaction between PGRN and PSAP was further confirmed by a large family-based genome-wide association study, in which polymorphisms in PSAP were shown to affect plasma PGRN levels (Nicholson et al 2016).…”

“…The interaction between PGRN and PSAP was further confirmed by a large family‐based genome‐wide association study, in which polymorphisms in PSAP were shown to affect plasma PGRN levels (Nicholson et al . ).…”

Progranulin, lysosomal regulation and neurodegenerative disease

“…A homozygous loss-of-function mutation in the gene encoding prosaposin leads to a lysosomal storage disease known as sphingolipidoses, which is similar to NCL in that it results from failed lysosomal macromolecular degradation 54,58 . Thus, in some ways, it is not surprising that progranulin and prosaposin form heterodimers 59,60 and that prosaposin can regulate both intracellular and secreted progranulin levels 61 (FIG. 2).…”