UMMS Affiliation

Department of Neurology

Publication Date


Document Type



Animals; Biological Markers; Cerebral Cortex; Endoplasmic Reticulum; Frontotemporal Dementia; Gene Expression Regulation; Glycoproteins; HEK293 Cells; Humans; Intercellular Signaling Peptides and Proteins; Mice; Microglia; Molecular Chaperones; Neurons; Protein Binding; Protein Disulfide-Isomerases; Protein Transport


Life Sciences | Medicine and Health Sciences | Neurology | Neuroscience and Neurobiology


The reduced production or activity of the cysteine-rich glycoprotein progranulin is responsible for about 20% of cases of familial frontotemporal dementia. However, little is known about the molecular mechanisms that govern the level and secretion of progranulin. Here we show that progranulin is expressed in mouse cortical neurons and more prominently in mouse microglia in culture and is abundant in the endoplasmic reticulum (ER) and Golgi. Using chemical crosslinking, immunoprecipitation, and mass spectrometry, we found that progranulin is bound to a network of ER Ca(2+)-binding chaperones including BiP, calreticulin, GRP94, and four members of the protein disulfide isomerase (PDI) family. Loss of ERp57 inhibits progranulin secretion. Thus, progranulin is a novel substrate of several PDI family proteins and modulation of the ER chaperone network may be a therapeutic target for controlling progranulin secretion.

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Copyright: © 2011 Almeida et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

DOI of Published Version



Almeida S, Zhou L, Gao F-B (2011) Progranulin, a Glycoprotein Deficient in Frontotemporal Dementia, Is a Novel Substrate of Several Protein Disulfide Isomerase Family Proteins. PLoS ONE 6(10): e26454. doi:10.1371/journal.pone.0026454. Link to article on publisher's site

Journal/Book/Conference Title

PloS one

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PubMed ID