Astrocytic pathology in Alpers' syndrome.
Alpers’ syndrome
Aquaporin 4 (AQP4)
GFAP
Glutamine synthetase (GS)
Kir4.1
Mitochondrial Epilepsy
POLG
Reactive astrogliosis
Journal
Acta neuropathologica communications
ISSN: 2051-5960
Titre abrégé: Acta Neuropathol Commun
Pays: England
ID NLM: 101610673
Informations de publication
Date de publication:
31 05 2023
31 05 2023
Historique:
received:
23
03
2023
accepted:
11
05
2023
medline:
2
6
2023
pubmed:
1
6
2023
entrez:
31
5
2023
Statut:
epublish
Résumé
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
Identifiants
pubmed: 37259148
doi: 10.1186/s40478-023-01579-w
pii: 10.1186/s40478-023-01579-w
pmc: PMC10230702
doi:
Substances chimiques
DNA, Mitochondrial
0
Glial Fibrillary Acidic Protein
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
86Subventions
Organisme : Medical Research Council
ID : MR/S005021/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0400074
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 203105/Z/16/Z
Pays : United Kingdom
Informations de copyright
© 2023. The Author(s).
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