C-Terminus of Progranulin Interacts with the Beta-Propeller Region of Sortilin to Regulate Progranulin Trafficking

Yanqiu Zheng,Owen A Brady,Peter S Meng,Fenghua Hu,Yuxin Mao,Hitoshi Okazawa

doi:10.1371/journal.pone.0021023

Yanqiu Zheng, Owen A Brady + Show 4 more

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https://doi.org/10.1371/journal.pone.0021023

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Journal: PloS one	Publication Date: Jun 15, 2011
Citations: 117	License type: CC BY 4.0

Affiliation: Cornell University

Abstract

Progranulin haplo-insufficiency is a main cause of frontotemporal lobar degeneration (FTLD) with TDP-43 aggregates. Previous studies have shown that sortilin regulates progranulin trafficking and is a main determinant of progranulin level in the brain. In this study, we mapped the binding site between progranulin and sortilin. Progranulin binds to the beta-propeller region of sortilin through its C-terminal tail. The C-terminal progranulin fragment is fully sufficient for sortilin binding and progranulin C-terminal peptide displaces progranulin binding to sortilin. Deletion of the last 3 residues of progranulin (QLL) abolishes its binding to sortilin and also sortilin dependent regulation of progranulin trafficking. Since progranulin haplo-insufficiency results in FTLD, these results may provide important insights into future studies of progranulin trafficking and signaling and progranulin based therapy for FTLD.

Highlights

Frontotemporal lobar degeneration (FTLD) is one of the most prevalent forms of early onset dementia (45–65 years of age), second only to Alzheimer’s disease [1,2]
To determine which structural domain of sortilin is involved in progranulin binding, we expressed the beta-propeller region or the 10CC region of sortilin fused to the transmembrane domain of platelet derived growth factor receptor (PDGFR)
We show that the binding between progranulin and sortilin is mediated by the C-terminal tail of progranulin and the beta-propeller region of sortilin

Summary

Introduction

Frontotemporal lobar degeneration (FTLD) is one of the most prevalent forms of early onset dementia (45–65 years of age), second only to Alzheimer’s disease [1,2]. Clinical features of FTLD include memory deficits, behavioral abnormalities, personality changes and language impairments [3]. Mutations in the Progranulin (PGRN) gene were recently shown to be a common cause of FTLD and the major cause of FTLD with tau-negative ubiquitin positive inclusions [4,5,6]. 68 distinct PGRN mutations have been found in 229 families Ua.ac.be/FTDMutations), responsible for 5–10% of all FTLD cases. Most mutations result in a decrease in the amount of progranulin expressed or secreted, rather than a gain of toxicity [4,5]. Progranulin haplo-insufficiency is strongly associated with FTLD [4,5]

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