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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.

SUBMITTER: Nicholson AM

PROVIDER: S-EPMC4931318 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Prosaposin is a regulator of progranulin levels and oligomerization.

Nicholson Alexandra M AM Finch NiCole A NA Almeida Marcio M Perkerson Ralph B RB van Blitterswijk Marka M Wojtas Aleksandra A Cenik Basar B Rotondo Sergio S Inskeep Venette V Almasy Laura L Dyer Thomas T Peralta Juan J Jun Goo G Wood Andrew R AR Frayling Timothy M TM Fuchsberger Christian C Fowler Sharon S Teslovich Tanya M TM Manning Alisa K AK Kumar Satish S Curran Joanne J Lehman Donna D Abecasis Goncalo G Duggirala Ravindranath R Pottier Cyril C Zahir Haaris A HA Crook Julia E JE Karydas Anna A Mitic Laura L Sun Ying Y Dickson Dennis W DW Bu Guojun G Herz Joachim J Yu Gang G Miller Bruce L BL Ferguson Shawn S Petersen Ronald C RC Graff-Radford Neill N Blangero John J Rademakers Rosa R

Nature communications 20160630

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 ...[more]

PMID: 27356620

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Project description:Progranulin (PGRN) is a protein encoded by the GRN gene with multiple identified functions including as a neurotrophic factor, tumorigenic growth factor, anti-inflammatory cytokine and regulator of lysosomal function. A single mutation in the human GRN gene resulting in reduced PGRN expression causes types of frontotemporal lobar degeneration resulting in frontotemporal dementia. Prosaposin (PSAP) is also a multifunctional neuroprotective secreted protein and regulator of lysosomal function. Interactions of PGRN and PSAP affect their functional properties. Their roles in Alzheimer's disease (AD), the leading cause of dementia, have not been defined. In this report, we examined in detail the cellular expression of PGRN in middle temporal gyrus samples of a series of human brain cases (n =?45) staged for increasing plaque pathology. Immunohistochemistry showed PGRN expression in cortical neurons, microglia, cerebral vessels and amyloid beta (A?) plaques, while PSAP expression was mainly detected in neurons and A? plaques, and to a limited extent in astrocytes. We showed that there were increased levels of PGRN protein in AD cases and corresponding increased levels of PSAP. Levels of PGRN and PSAP protein positively correlated with amyloid beta (A?), with PGRN levels correlating with phosphorylated tau (serine 205) levels in these samples. Although PGRN colocalized with lysosomal-associated membrane protein-1 in neurons, most PGRN associated with A? plaques did not. A? plaques with PGRN and PSAP deposits were identified in the low plaque non-demented cases suggesting this was an early event in plaque formation. We did not observe PGRN-positive neurofibrillary tangles. Co-immunoprecipitation studies of PGRN from brain samples identified only PSAP associated with PGRN, not sortilin or other known PGRN-binding proteins, under conditions used. Most PGRN associated with A? plaques were immunoreactive for PSAP showing a high degree of colocalization of these proteins that did not change between disease groups. As PGRN supplementation has been considered as a therapeutic approach for AD, the possible involvement of PGRN and PSAP interactions in AD pathology needs to be further considered.

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Prosaposin is a regulator of progranulin levels and oligomerization.

Publications

Prosaposin is a regulator of progranulin levels and oligomerization.

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