Activated microglia and neuroinflammation as a pathogenic mechanism in Leigh syndrome

Nastaran Daneshgar; Mariah Leidinger; Stephanie Le; Marco Hefti; Alessandro Prigione; Dao-Fu Dai

doi:10.3389/fnins.2022.1068498

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Activated microglia and neuroinflammation as a pathogenic mechanism in Leigh syndrome

Journal article

Open access

Peer reviewed

Activated microglia and neuroinflammation as a pathogenic mechanism in Leigh syndrome

Nastaran Daneshgar, Mariah Leidinger, Stephanie Le, Marco Hefti, Alessandro Prigione and Dao-Fu Dai

Frontiers in neuroscience, Vol.16, 1068498

01/18/2023

DOI: 10.3389/fnins.2022.1068498

PMCID: PMC9889986

PMID: 36741056

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Abstract

Neuroinflammation is one of the main mechanisms leading to neuronal death and dysfunction in neurodegenerative diseases. The role of microglia as primary mediators of inflammation is unclear in Leigh syndrome (LS) patients. This study aims to elucidate the role of microglia in LS progression by a detailed multipronged analysis of LS neuropathology, mouse and human induced pluripotent stem cell models of Leigh syndrome. We described brain pathology in three cases of Leigh syndrome and performed immunohistochemical staining of autopsy brain of LS patients. We used Ndufs4-/- mouse to study the effect of microglial partial ablation using pharmacologic approach. Human induced pluripotent stem cell-derived neurons and brain organoid with Ndufs4 mutation were used to investigate the neuroinflammation in LS. We reported a novel observation of marked increase of Iba-1 cells with features of activated microglia, in various parts of brain in postmortem neuropathological examinations of 3 Leigh syndrome patients. Using Ndufs4-/- mouse model for Leigh Syndrome, we showed that depletion of microglia by Pexidartinib initiated at the symptom onset improved neurological function and significantly extended lifespan. Ndufs4 mutant LS brain organoid had elevated NLRP3 and IL6 pro-inflammatory pathways. Ndufs4-mutant LS iPSC neurons were more susceptible to glutamate excitotoxicity, which was further potentiated by IL-6. Our findings of LS human brain pathology, Ndufs4-deficient mouse and iPSC models of LS suggest a critical role of activated microglia in the progression of LS encephalopathy. This study suggests a potential clinical application of microglial inhibition and immunosuppression during the active phase of Leigh Syndrome.

Alzheimers Disease

Animal Models

Brain

Cell Culture

Immunosuppression

Inflammation

Neurodegenerative Diseases

Neurons

Neuropathology

Pathology

Stem Cells

Ablation

Autopsy

Blood vessels

Brain stem

Encephalopathy

Excitotoxicity

Interleukin 6

Life span

Microglia

Mutants

Organoids

Pluripotency

Details

Title: Subtitle: Activated microglia and neuroinflammation as a pathogenic mechanism in Leigh syndrome
Creators: Nastaran Daneshgar - Roy J. and Lucille A. Carver College of Medicine
Mariah Leidinger
Stephanie Le
Marco Hefti
Alessandro Prigione
Dao-Fu Dai
Resource Type: Journal article
Publication Details: Frontiers in neuroscience, Vol.16, 1068498
DOI: 10.3389/fnins.2022.1068498
PMID: 36741056
PMCID: PMC9889986
NLM abbreviation: Front Neurosci
ISSN: 1662-4548
eISSN: 1662-453X
Publisher: Frontiers Research Foundation
Grant note: DOI: 10.13039/100000002, name: National Institutes of Health
Language: English
Date published: 01/18/2023
Academic Unit: Pathology; Iowa Neuroscience Institute; Radiation Oncology
Record Identifier: 9984362359602771

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