Lack of a site-specific phosphorylation of Presenilin 1 disrupts microglial gene networks and progenitors during development.

Jose Henrique Ledo,Paul Greengard,Diego Mourão-Sá,Olga G Troyanskaya,Victor Bustos,Luka Mesin,Ran Zhang,Estefania P Azevedo,Ramon Trullas

doi:10.1371/journal.pone.0237773

Jose Henrique Ledo, Paul Greengard + Show 7 more

Open Access

https://doi.org/10.1371/journal.pone.0237773

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Abstract

Microglial cells play a key role in brain homeostasis from development to adulthood. Here we show the involvement of a site-specific phosphorylation of Presenilin 1 (PS1) in microglial development. Profiles of microglia-specific transcripts in different temporal stages of development, combined with multiple systematic transcriptomic analysis and quantitative determination of microglia progenitors, indicate that the phosphorylation of PS1 at serine 367 is involved in the temporal dynamics of microglial development, specifically in the developing brain rudiment during embryonic microgliogenesis. We constructed a developing brain-specific microglial network to identify transcription factors linked to PS1 during development. Our data showed that PS1 functional connections appear through interaction hubs at Pu.1, Irf8 and Rela-p65 transcription factors. Finally, we showed that the total number of microglia progenitors was markedly reduced in the developing brain rudiment of embryos lacking PS1 phosphorylation compared to WT. Our work identifies a novel role for PS1 in microglial development.

Highlights

Presenilin 1 (Psen1 gene–PS1 protein) is the catalytic subunit of γ-secretase, an enzyme complex responsible for the cleavage of an extensive number substrates [1,2]
Considering all microglial developmental stages analyzed, GO enrichment revealed that the most common processes impaired in Psen1KI/KI microglia compared to control microglia are related to cell differentiation, phagocytosis and immune response (Fig 1B)
We observed alterations in pathways related to immune response, phagocytosis and behavior in the Psen1KI/KI microglia from brain rudiment, neonates, and adults compared to WT controls (Fig 1B)

Summary

Introduction

Presenilin 1 (Psen gene–PS1 protein) is the catalytic subunit of γ-secretase, an enzyme complex responsible for the cleavage of an extensive number substrates [1,2]. Γ-secretase is responsible for the conversion of the amyloid precursor protein (APP) into amyloid-β (Aβ) peptide [3]. PS1 has been most studied in the context of Alzheimer’s disease (AD), largely because mutations that cause early onset of AD are found most frequently in Psen gene and PS1 plays a key role in Aβ production. In addition to its key role in AD, PS1 plays a fundamental role in early brain development [2, 4].

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