Abstract
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 Ca2+-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.
Highlights
Frontotemporal lobar degeneration (FTLD), the most common cause of dementia before the age of 60 years [1], causes behavioral and cognitive abnormalities, and up to 40% of patients have a family history of dementia [1,2]
Through biochemical approaches, we found that PGRN is a novel substrate of four protein disulfide isomerase (PDI) family proteins, raising the possibility that modulation of the endoplasmic reticulum (ER) chaperone network may be a therapeutic target for controlling progranulin secretion
Identification of PGRN-Interacting Proteins To identify regulators of PGRN secretion and PGNR-interacting proteins, we constructed fusion proteins whose expression is controlled by the CMV promoter, including mouse PGRN (mPGRN)-tagged with alkaline phosphatase (AP) or HA
Summary
Frontotemporal lobar degeneration (FTLD), the most common cause of dementia before the age of 60 years [1], causes behavioral and cognitive abnormalities, and up to 40% of patients have a family history of dementia [1,2]. PRGN mutations are a major cause of the disease, and genetic evidence suggests that haploinsufficiency is involved, since disease-associated mutations in PGRN often lead to reduced PGRN production or activity [3,4,5,6,7,8]. It is not known how such reductions lead to neurodegeneration. Loss of microRNA-29b activity increases the levels of intracellular and secreted PGRN in 3T3 cells [10]. Extracellular levels of PGRN are influenced by its rate of uptake through sortilin-mediated endocytosis [14,15]
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