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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 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 is an attractive 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. 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 Ripk1’s kinase activity and occurs through a novel signaling pathway. These data support targeting Ripk1 as a therapeutic strategy in both AD and FTD.

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