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

J Biol Chem. 2017 Feb 24;292(8):3262-3272. doi: 10.1074/jbc.M116.752006. Epub 2017 Jan 9.

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 GRN, the gene encoding PGRN, cause frontotemporal dementia (FTD), and a GRN 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 (Ripk1) 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 Grn-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.

Keywords: Alzheimer disease; Ripk1; frontotemporal dementia; neurobiology; neurodegeneration; neurodegenerative disease; neurological disease; progranulin.

MeSH terms

  • Alzheimer Disease / metabolism
  • Animals
  • Cell Line
  • Cells, Cultured
  • Granulins
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Mice
  • Neurons / metabolism*
  • Protein Biosynthesis
  • RNA Interference
  • RNA, Messenger / genetics
  • RNA, Small Interfering / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*

Substances

  • Granulins
  • Grn protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • RNA, Messenger
  • RNA, Small Interfering
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk1 protein, mouse