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Astrocytic pathology in Alpers’ syndrome

Lookup NU author(s): Laura Alexandra Smith, Dr Chun ChenORCiD, Dr Nichola Lax, Professor Robert Taylor, Dr Daniel ErskineORCiD, Professor Bobby McFarlandORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

Refractory epilepsy is the main neurological manifestation of Alpers’ syndrome, a severe childhood-onset mitochondrial disease caused by bi-allelic pathogenic variants in the mitochondrial DNA (mtDNA) polymerase gamma gene (POLG). The pathophysiological mechanisms underpinning neuronal hyperexcitabilty leading to seizures in Alpers’ syndrome remain unknown. However, pathological changes to reactive astrocytes are hypothesised to exacerbate neural dysfunction and seizure-associated cortical activity in POLG-related disease. Therefore, we sought to phenotypically characterise astrocytic pathology in Alpers’ syndrome. We performed a detailed quantitative investigation of reactive astrocytes in post-mortem neocortical tissues from thirteen patients with Alpers’ syndrome, eight neurologically normal controls and five sudden unexpected death in epilepsy (SUDEP) patients, to control for generalised epilepsy-associated astrocytic pathology. Immunohistochemistry to identify glial fibrillary acidic protein (GFAP)-reactive astrocytes revealed striking reactive astrogliosis localised to the primary visual cortex of Alpers’ syndrome tissues, characterised by abnormal-appearing hypertrophic astrocytes. Phenotypic characterisation of individual GFAP-reactive astrocytes demonstrated decreased abundance of mitochondrial oxidative phosphorylation (OXPHOS) proteins and altered expression of key astrocytic proteins including Kir4.1 (subunit of the inwardly rectifying K+ ion channel), AQP4 (astrocytic water channel) and glutamine synthetase (enzyme that metabolises glutamate). These phenotypic astrocytic changes were typically different from the pathology observed in SUDEP tissues, suggesting alternative mechanisms of astrocytic dysfunction between these epilepsies. Crucially, our findings provide further evidence of occipital lobe involvement in Alpers’ syndrome and support the involvement of reactive astrocytes in the pathogenesis of POLG-related disease.


Publication metadata

Author(s): Smith LA, Chen C, Lax NZ, Taylor RW, Erskine D, McFarland R

Publication type: Article

Publication status: Published

Journal: Acta Neuropathologica Communications

Year: 2023

Issue: 11

Online publication date: 31/05/2023

Acceptance date: 11/05/2023

Date deposited: 31/05/2023

ISSN (electronic): 2051-5960

Publisher: BioMed Central Ltd.

URL: https://doi.org/10.1186/s40478-023-01579-w

DOI: 10.1186/s40478-023-01579-w


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Funding

Funder referenceFunder name
203105/Z/16/ZWellcome Trust
Alzheimer’s Research UK
ARUK-SRF2022A-006
Lily Foundation
G0800674
MR/S005021/1Medical Research Council (MRC)
Pathological Society and Mito Foundation
Ryan Stanford Appeal
NIHR

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