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.
journal_name
Nat Communjournal_title
Nature communicationsauthors
Nicholson AM,Finch NA,Almeida M,Perkerson RB,van Blitterswijk M,Wojtas A,Cenik B,Rotondo S,Inskeep V,Almasy L,Dyer T,Peralta J,Jun G,Wood AR,Frayling TM,Fuchsberger C,Fowler S,Teslovich TM,Manning AK,Kumar S,Curradoi
10.1038/ncomms11992subject
Has Abstractpub_date
2016-06-30 00:00:00pages
11992issn
2041-1723pii
ncomms11992journal_volume
7pub_type
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