In vivo magnetic resonance spectroscopy in the brain of Cdkl5 null mice reveals a metabolic profile indicative of mitochondrial dysfunctions.
5’-AMP-activated protein kinase
CDKL5 deficiency disorder (CDD)
Cdkl5 mouse model
MRI/MRS studies
biomarkers
mitochondria
Journal
Journal of neurochemistry
ISSN: 1471-4159
Titre abrégé: J Neurochem
Pays: England
ID NLM: 2985190R
Informations de publication
Date de publication:
05 2021
05 2021
Historique:
revised:
24
10
2020
received:
20
05
2020
accepted:
07
01
2021
pubmed:
16
1
2021
medline:
22
6
2021
entrez:
15
1
2021
Statut:
ppublish
Résumé
Mutations in the X-linked CDKL5 gene cause CDKL5 deficiency disorder (CDD), a severe neurodevelopmental condition mainly characterized by infantile epileptic encephalopathy, intellectual disability, and autistic features. The molecular mechanisms underlying the clinical symptoms remain largely unknown and the identification of reliable biomarkers in animal models will certainly contribute to increase our comprehension of CDD as well as to assess the efficacy of therapeutic strategies. Here, we used different Magnetic Resonance (MR) methods to disclose structural, functional, or metabolic signatures of Cdkl5 deficiency in the brain of adult mice. We found that loss of Cdkl5 does not cause cerebral atrophy but affects distinct brain areas, particularly the hippocampus. By in vivo proton-MR spectroscopy (MRS), we revealed in the Cdkl5 null brain a metabolic dysregulation indicative of mitochondrial dysfunctions. Accordingly, we unveiled a significant reduction in ATP levels and a decrease in the expression of complex IV of mitochondrial electron transport chain. Conversely, the number of mitochondria appeared preserved. Importantly, we reported a significant defect in the activation of one of the major regulators of cellular energy balance, the adenosine monophosphate-activated protein kinase (AMPK), that might contribute to the observed metabolic impairment and become an interesting therapeutic target for future preclinical trials. In conclusion, MRS revealed in the Cdkl5 null brain the presence of a metabolic dysregulation suggestive of a mitochondrial dysfunction that permitted to foster our comprehension of Cdkl5 deficiency and brought our interest towards targeting mitochondria as therapeutic strategy for CDD.
Substances chimiques
Protein Serine-Threonine Kinases
EC 2.7.11.1
CDKL5 protein, mouse
EC 2.7.11.22
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1253-1269Informations de copyright
© 2021 International Society for Neurochemistry.
Références
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