Progranulin inhibits phospholipase sPLA2-IIA to control neuroinflammation.
bioRxiv
; 2023 Apr 06.
Article
em En
| MEDLINE
| ID: mdl-37066328
ABSTRACT
Mutations in the granulin (GRN) gene, resulting in haploinsufficiency of the progranulin (PGRN) protein, are a leading cause of frontotemporal lobar degeneration (FTLD) and PGRN polymorphisms are associated with Alzheimer's disease (AD) and Parkinson's disease (PD). PGRN is a key regulator of microglia-mediated inflammation but the mechanism is still unknown. Here we report that PGRN interacts with sPLA2-IIA, a secreted phospholipase involved in inflammatory responses, to downregulate sPLA2-IIA activities and levels. sPLA2-IIA expression modifies PGRN deficiency phenotypes in mice and sPLA2-IIA inhibition rescues inflammation and lysosomal abnormalities in PGRN deficient mice. Furthermore, FTLD patients with GRN mutations show increased levels of sPLA2-IIA in astrocytes. Our data support sPLA2-IIA as a critical target for PGRN and a novel therapeutic target for FTLD-GRN.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Revista:
BioRxiv
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Estados Unidos
País de publicação:
EEUU
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ESTADOS UNIDOS
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ESTADOS UNIDOS DA AMERICA
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EUA
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UNITED STATES
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UNITED STATES OF AMERICA
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US
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USA