The Receptor-interacting Serine/Threonine Protein Kinase 1 (RIPK1) Regulates Progranulin Levels

Abstract

Progranulin (PGRN), a secreted growth factor, is a key regulator of inflammation and is genetically linked to two common and devastating neurodegenerative diseases. Haploinsufficiency mutations in , the gene encoding PGRN, cause frontotemporal dementia (FTD), and a SNP confers significantly increased risk for Alzheimer's disease (AD). Because cellular and animal data indicate that increasing PGRN can reverse phenotypes of both FTD and AD, modulating PGRN level has been proposed as a therapeutic strategy for both diseases. However, little is known about the regulation of PGRN levels. In this study, we performed an siRNA-based screen of the kinome to identify genetic regulators of PGRN levels in a rodent cell-based model system. We found that knocking down receptor-interacting serine/threonine protein kinase 1 () increased both intracellular and extracellular PGRN protein levels by increasing the translation rate of PGRN without affecting mRNA levels. We observed this effect in Neuro2a cells, wild-type primary mouse neurons, and -haploinsufficient primary neurons from an FTD mouse model. We found that the effect of RIPK1 on PGRN is independent of the kinase activity of RIPK1 and occurs through a novel signaling pathway. These data suggest that targeting RIPK1 may be a therapeutic strategy in both AD and FTD.

Atxn2-CAG100-KnockIn mouse spinal cord shows progressive TDP43 pathology associated with cholesterol biosynthesis suppression

“…PGRN abundance is modulated in response to RIPK1-mediated phosphorylation [118], whose activation can sense viral or toxic nucleotides via the toll-like receptor TLR3 [93, 129], drives pro-inflammatory necroptosis [234], and is implicated in ALS [81, 230]. Consistent with these reports, enhanced RIPK1 protein levels were observed in the spinal cord of Atxn2 -CAG100-KIN mice, possibly with a 1.4-fold abundance already at 3 months, but achieving significance only for the 1.5-fold increase at the age of 14 months (Figure 3C/D).…”

Pazopanib Reduces Phosphorylated Tau Levels and Alters Astrocytes in a Mouse Model of Tauopathy

“…Furthermore, another group has shown pazopanib putatively shares similar acetylcholine esterase interactions with a known AD drug donepezil (Aricept®) [90] and restores cognitive deficits in rats insulted with quinolinic acid and treated with 15 mg/kg pazopanib (less at 3.75 and 0.94 mg/kg doses). Moreover, pazopanib targets receptor-interacting serine/threonine-protein kinase 1 (RIPK1) [91], a protein when inhibited leads to increased levels of the growth factor progranulin [92]. Increasing progranulin levels has long been believed to be a treatment method for AD and frontotemporal dementia [93-95].…”

Progranulin in neurodegenerative dementia

“…Ripk1 has been reported to be a genetic regulator of Grn in Neuro2a cells, microglial‐like BV‐2 cells, wild‐type primary neurons, and Grn ‐haploinsufficient primary neurons. It increases both intracellular and extracellular PGRN protein levels by increasing the translation rate of PGRN without affecting mRNA levels (Mason et al., 2017). IL‐6 stimulates GRN expression in hepatocellular carcinoma and cholangiocarcinoma cells partly by activating extracellular signal‐regulated kinase (Erk)/CCAAT/enhancer‐binding protein β (C/EBPβ) signaling ( Frampton et al., 2012; Liu et al., 2016).…”

“…This drug crosses the blood‐brain barrier more easily than SAHA (Tsai & Boxe r, 2016). Knocking down Ripk1 increases both intracellular and extracellular PGRN protein levels (Mason et al., 2017); thus, targeting RIPK1 may be a therapeutic strategy for PGRN deficit‐related dementia (Degterev et al., 2019; Mifflin et al., 2020; Yuan et al., 2019). Denali Therapeutics Inc. is vigorously developing small‐molecule inhibitors of RIPK1.…”