A Multifaceted Role of Progranulin in Regulating Amyloid-beta Dynamics and Responses

Overview

Journal Life Sci Alliance

Specialties Biochemistry
Biology
Cell Biology
Molecular Biology

Date 2021 Jun 9

PMID 34103390

Citations 5

Authors

Huan Du

Man Ying Wong

Tingting Zhang

Mariela Nunez Santos

Charlene Hsu

Junke Zhang

Haiyuan Yu

Wenjie Luo

Fenghua Hu

Affiliations

Soon will be listed here.

Abstract

Haploinsufficiency of progranulin (PGRN) is a leading cause of frontotemporal lobar degeneration (FTLD). PGRN polymorphisms are associated with Alzheimer's disease. PGRN is highly expressed in the microglia near Aβ plaques and influences plaque dynamics and microglial activation. However, the detailed mechanisms remain elusive. Here we report that PGRN deficiency reduces human APP and Aβ levels in the young male but not female mice. PGRN-deficient microglia exhibit increased expression of markers associated with microglial activation, including CD68, galectin-3, TREM2, and GPNMB, specifically near Aβ plaques. In addition, PGRN loss leads to up-regulation of lysosome proteins and an increase in the nuclear localization of TFE3, a transcription factor involved in lysosome biogenesis. Cultured PGRN-deficient microglia show enhanced nuclear translocation of TFE3 and inflammation in response to Aβ fibril treatment. Taken together, our data revealed a sex- and age-dependent effect of PGRN on APP metabolism and a role of PGRN in regulating lysosomal activities and inflammation in plaque-associated microglia.

Citing Articles

Mitochondrial dysfunction, cause or consequence in neurodegenerative diseases?.

Van Acker Z, Leroy T, Annaert W Bioessays. 2024; 47(1):e2400023.

PMID: 39367555 PMC: 11662158. DOI: 10.1002/bies.202400023.

Progranulin and GPNMB: interactions in endo-lysosome function and inflammation in neurodegenerative disease.

Gillett D, Wallings R, Uriarte Huarte O, Tansey M J Neuroinflammation. 2023; 20(1):286.

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Progranulin deficiency results in sex-dependent alterations in microglia in response to demyelination.

Zhang T, Feng T, Wu K, Guo J, Nana A, Yang G Acta Neuropathol. 2023; 146(1):97-119.

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Progranulin loss results in sex-dependent dysregulation of the peripheral and central immune system.

Houser M, Uriarte Huarte O, Wallings R, Keating C, MacPherson K, Herrick M Front Immunol. 2023; 13:1056417.

PMID: 36618392 PMC: 9814971. DOI: 10.3389/fimmu.2022.1056417.

Differential regulation of progranulin derived granulin peptides.

Zhang T, Du H, Nunez Santos M, Wu X, Pagan M, Trigiani L Mol Neurodegener. 2022; 17(1):15.

PMID: 35120524 PMC: 8815130. DOI: 10.1186/s13024-021-00513-9.

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