Defects in mitochondria — cells’ powerhouses — and nerve cell damage resulting from increased oxidative stress may account for the some of the cellular defects observed in Rett syndrome and CDKL5 deficiency disorder, a related neurodevelopmental disorder.
The study, “Aberrant mitochondrial function in patient-derived neural cells from CDKL5 deficiency disorder and Rett Syndrome” was published in the journal Human Molecular Genetics.
Rett syndrome (RTT) and CDKL5 deficiency disorder (CDD) are neurodevelopmental disorders that predominantly affect females and result in overlapping clinical manifestations, including intellectual disability, infantile spasms, and seizures.
They are caused by mutations in genes located on the X chromosome (one of the sex chromosomes), which are involved in a cellular pathway important for the growth of nerve cells and the transmission of chemical signals at the connections (synapses) between them.
While the similarities between the diseases are recognized, the shared molecular mechanisms of disease have yet to be discovered.
Several lines of research have suggested problems in the metabolism of cells, in particular exposure to oxidative stress and deficiencies in mitochondria, in both diseases.
Oxidative stress is an imbalance between the production of free radicals and the ability of cells to detoxify them. These free radicals, or reactive oxygen species (ROS), are harmful to the cells and are associated with a number of diseases.
Importantly, nerve cells — those mainly affected in Rett — may be particularly susceptible to oxidative stress, as the brain has few active defense pathways against ROS (antioxidative activity).
To uncover how these alterations are linked to Rett and CDD, researchers at Boston’s Massachusetts General Hospital and Harvard Medical School investigated mitochondrial function in cells from RTT and CDD patients.
The team used human central nervous system (CNS; the brain and spinal cord) cells called neural progenitor cells (NPCs). NPCs are the progenitor cells that give rise to many of the glial and nerve cell types that populate the CNS. In humans, they are present and proliferate mostly during embryonic development through birth.
Researchers generated NPCs in the lab from skin biopsies of a 25-year-old female RTT patient and a 2-year-old girl with CDD. They then looked at mitochondria to understand whether there were any changes in its structure and to look for the presence of potentially toxic molecules in each of the cell lines.
Compared to a healthy cell line (control), Rett and CDKL5 deficiency disorder NPCs had increased rates of respiration — the process through which most of the energy in our cells is produced. Respiration occurs inside mitochondria.
Contrary to CDD, cells derived from the patient with Rett had a normal distribution of electrical charges across the mitochondrial membrane (essential for maintaining mitochondria’s integrity).
In addition, a greater production of reactive oxygen species (ROS) was observed in the Rett cell line. Conversely, CDD cells did not demonstrate any significant increase in ROS generation, suggesting that the observed increase in oxidative stress is restricted to Rett patients.
Overall, the findings indicate “a distinct difference of mitochondrial dysfunction between CDD- and RTT-patient-derived NPCs,” the researchers stated.
Given the fundamental role of NPCs during development, these findings also suggest that the mitochondrial changes underpinning Rett and CDD start early during development.
“This makes [NPCs] important tools for phenotypic screening of compounds for developing novel therapies toward neurological disorders such as CDD and RTT,” the researchers added.
An earlier Phase 2 trial (NCT01822249) that addressed the potential benefits of targeting oxidative stress in 24 Rett patients showed that treatment with a vitamin E derivative (EPI-743, vatiquinone) that holds antioxidant properties could improve mitochondrial respiratory function. However, it did not significantly improve patient-reported disease scores.