@article{e206aeebfb7f4748a19fd25e29692bb7,
title = "Pathogenic Signal Sequence Mutations in Progranulin Disrupt SRP Interactions Required for mRNA Stability",
abstract = "Cells have evolved quality control pathways to prevent the accumulation of improperly localized proteins, which are often toxic. One of these pathways, regulation of aberrant protein production (RAPP), recognizes aberrant secretory proteins during translation and degrades the associated mRNA. Here, we demonstrate endogenous RAPP substrates. Haploinsufficiency of the secretory protein progranulin (GRN) is associated with the neurodegenerative disease frontotemporal lobar degeneration (FTLD). Our results show FTLD-associated GRN mutations W7R and A9D disrupt co-translational interaction with a targeting factor, signal recognition particle (SRP). This triggers RAPP and initiates specific mRNA degradation. Conversely, wild-type GRN and the naturally occurring polymorphism V5L GRN are efficiently expressed and secreted. Thus, RAPP plays a role in the molecular pathology of A9D GRN and W7R GRN. Progranulin mutations, which reduce its secretion, cause the disease FTLD (frontotemporal lobar degeneration). Here, Pinarbasi et al. show that one such mutation, A9D, prevents recruitment of the trafficking factor SRP (signal recognition particle). This triggers a quality control response, which results in degradation of A9D mRNA.",
keywords = "FTLD, SRP, mRNA degradation, mRNA stability, secretion, signal recognition, translation",
author = "Pinarbasi, {Emile S.} and Karamyshev, {Andrey L.} and Tikhonova, {Elena B.} and Wu, {I. Hui} and Henry Hudson and Thomas, {Philip J.}",
note = "Funding Information: Authors thank Jerry Shay for help culturing patient fibroblasts. This study used samples from the NINDS Cell Line Repository: sample number ND40082. This research was supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (DK049835) to P.J.T. and by the Center of Excellence for Translational Neuroscience and Therapeutics (CTNT) grant PN-CTNT 2017-05 AKHRJDHW and the National Institute of Neurological Disorders and Stroke of the NIH under award number R03NS102645 to A.L.K. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Funding Information: Authors thank Jerry Shay for help culturing patient fibroblasts. This study used samples from the NINDS Cell Line Repository: sample number ND40082. This research was supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases ( DK049835 ) to P.J.T. and by the Center of Excellence for Translational Neuroscience and Therapeutics (CTNT) grant PN-CTNT 2017-05 AKHRJDHW and the National Institute of Neurological Disorders and Stroke of the NIH under award number R03NS102645 to A.L.K. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Publisher Copyright: {\textcopyright} 2018 The Author(s)",
year = "2018",
month = jun,
day = "5",
doi = "10.1016/j.celrep.2018.05.003",
language = "English (US)",
volume = "23",
pages = "2844--2851",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "10",
}