In vivo magnetic resonance spectroscopy in the brain of Cdkl5 null mice reveals a metabolic profile indicative of mitochondrial dysfunctions. Issue 4 (2nd February 2021)

• Record Type: Journal Article
• Authors: Carli, Sara; Chaabane, Linda; Butti, Clarissa; De Palma, Clara; Aimar, Patrizia; Salio, Chiara; Vignoli, Aglaia; Giustetto, Maurizio; Landsberger, Nicoletta; Frasca, Angelisa
• Is Part Of: Journal of neurochemistry. Volume 157:Issue 4(2021)
• Page Start: 1253
• Page End: 1269
• Publication Date: 2021-02-02
• Subjects: 5'‐AMP‐activated protein kinase -- biomarkers -- CDKL5 deficiency disorder (CDD) -- Cdkl5 mouse model -- mitochondria -- MRI/MRS studies; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.15300
• Languages: English
• ISSNs: 0022-3042

Abstract

Abstract: 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. Abstract : CDKL5 deficiency disorder (CDD) is a severe neurodevelopmental disorder whose pathophysiology remains mainly uncharacterized and effective therapies are still lacking. Cdkl5 null mice are instrumental for the study of the disease and the identification of novel therapies. To reinforce our comprehension of CDD and identify biomarkers, we tested different approaches of Magnetic Resonance Imaging applied to null mice. We show that the CDD brain suffers from generalized hyperactivity and a hippocampal neurochemical signature mirroring mitochondrial dysfunction. Accordingly, ATP levels and electron transport chain are defective together with AMPK phosphorylation, indicating a novel therapeutic target. Image created by BioRender.com