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Analysis of Brain Mitochondria Using Serial Block-Face Scanning Electron Microscopy
Published on: July 9, 2016
Abnormalities of mitochondrial dynamics and bioenergetics in neuronal cells from CDKL5 deficiency disorder
Nicole J Van Bergen1, Sean Massey2, Tegan Stait2
1Brain and Mitochondrial Research Group, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia.
Insights
Mitochondrial dysfunction contributes to CDKL5 deficiency disorder (CDD), a severe neurodevelopmental condition. This study reveals impaired mitochondrial function and transport in CDD neurons, suggesting new therapeutic targets.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- CDKL5 deficiency disorder (CDD) is a severe neurodevelopmental disorder caused by mutations in the CDKL5 gene.
- Current treatments for CDD are symptomatic, highlighting the need for targeted therapies.
- Mitochondrial dysfunction is increasingly implicated in CDD, but requires further investigation.
Purpose of the Study:
- To investigate the impact of CDKL5 mutations on neuronal cellular function, specifically mitochondrial health.
- To utilize patient-derived stem cells and gene-corrected controls for precise analysis.
Main Methods:
- Generation of human induced pluripotent stem cells (iPSCs) from CDD patients with a specific CDKL5 mutation (p.Arg59*) and isogenic controls.
- Differentiation of iPSCs into neurons for cellular analysis.
- Quantitative proteomics and mitochondrial bioenergetics assays to assess mitochondrial function and dynamics.
Main Results:
- CDKL5-deficient neurons exhibited significant mitochondrial defects.
- Reduced activity of mitochondrial respiratory chain complexes was observed.
- Impaired mitochondrial trafficking velocity and increased stationary mitochondria were detected.
Conclusions:
- Mitochondrial dysfunction is a key contributor to the pathology of CDKL5 deficiency disorder.
- Targeting mitochondrial dysfunction presents a promising therapeutic strategy for CDD.
- Further research into mitochondrial pathways is crucial for developing effective CDD treatments.
Abstract:
CDKL5 deficiency disorder (CDD) is a rare neurodevelopmental disorder caused by pathogenic variants in the Cyclin-dependent kinase-like 5 (CDKL5) gene, resulting in dysfunctional CDKL5 protein. It predominantly affects females and causes seizures in the first few months of life, ultimately resulting in severe intellectual disability. In the absence of targeted therapies, treatment is currently only symptomatic. CDKL5 is a serine/threonine kinase that is highly expressed in the brain, with a critical role in neuronal development. Evidence of mitochondrial dysfunction in CDD is gathering, but has not been studied extensively. We used human patient-derived induced pluripotent stem cells with a pathogenic truncating mutation (p.Arg59*) and CRISPR/Cas9 gene-corrected isogenic controls, differentiated into neurons, to investigate the impact of CDKL5 mutation on cellular function. Quantitative proteomics indicated mitochondrial defects in CDKL5 p.Arg59* neurons, and mitochondrial bioenergetics analysis confirmed decreased activity of mitochondrial respiratory chain complexes. Additionally, mitochondrial trafficking velocity was significantly impaired, and there was a higher percentage of stationary mitochondria. We propose mitochondrial dysfunction is contributing to CDD pathology, and should be a focus for development of targeted treatments for CDD.
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