Work

Pathogenic Signal Sequence Mutations in Progranulin Disrupt SRP Interactions Required for mRNA Stability

Year: 2018

Type: article

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.

Source: Cell Reports

DOI: 10.1016/j.celrep.2018.05.003

Authors: Emile S. Pinarbasi, Andrey L. Karamyshev, Elena B. Tikhonova, I-Hui Wu, Henry Hudson, Philip J. Thomas

Institutions: The University of Texas Southwestern Medical Center, Texas Tech University, Texas Tech University Health Sciences Center

Language: English

Topic: Amyotrophic Lateral Sclerosis Research

Subfield: Neurology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $5,620