Growth retardation, short stature, microcephaly (abnormally small head size), vision problems, impaired nervous system, abnormal photosensitivity and premature ageing are the basic symptoms that characterise the rare neurodegenerative disorder Neill-Dingwall syndrome, more commonly known as the Cockayne syndrome (CS).
Eighty percent of CS cases are caused by mutations in a gene called ERCC6, with codes for a protein called Cockayne Syndrome B (CSB). ERCC8 & ERCC6 mutations are responsible for CSA & CSB type respectively.
The ERCC6 gene is responsible for the production of CSB protein which in turn repairs damage due to UV radiation in active genes. Once mutated, a CSB protein malfunction or an abnormal short version occurs. CS has poor prognosis and no cure yet, and most patients with this syndrome do not survive beyond their twenties. Previous trials of working on mouse models failed because they do not show the classical neurological symptoms.
Therefore, scientists at the UC San Diego School of Medicine departments of Pediatrics and Cellular and Molecular Medicine, lead by associate professor Alysson R. Muotri designed a human stem cell derived in vitro cellular model to get a clear understanding of what is occurring in the human brain that could further help in formulating effective therapeutics to combat the disease.
They took skin cells from 2 CS patients, reverted them to induced pluripotent stem cells(iPSCs) & reprogrammed those cells to differentiate as neurons & neural progenitor cells.The neurons subsequently formed functioning networks, popularly dubbed “mini-brains.” These neurons formed neural networks which showed a marked reduction in synaptic density, synchrony and alteration in electrophysiological activity when compared with neuronal networks from control models. Pathways which are linked to synapse formation and maintenance also showed dysregulation.
Says Muotri, “This work provides an alternative to existing models for studying neural-specific aspects of CS, It reveals that CSB protein is required for normal neuronal function” and stated that this experiment is a better alternative than the previous models to study the neural aspects of Cockayne syndrome.
The original publication can be accessed here.