Linking the poly alanine brain diseases to the ubiquitin transfer system

Central Congenital Hypoventilation Syndrome (CCHS) is caused by a mutation in the PHOX2B gene, a key transcription factor in the development of the autonomic nervous system (ANS), a system that controls non-voluntary body functions such as breathing, digestion and heart rate. PHOX2B and eight other nuclear proteins that cause various neural disorders have a poly-alanine tract. In these disorders, a mutation that expands the poly-alanine tract causes the disease.  

The lab identified a poly-alanine that is also present in one of the enzymes of the ubiquitin transfer system. In a healthy condition, this poly-alanine stretch is required for enzyme recognition enabling proper ubiquitin transfer to target proteins, such as those involved in neural development, thereby controlling their degradation.

In a disease, such as in CCHS, the teams discovered that the expansion mutation of the poly-alanine tract in PHOX2B (and in other poly-alanine disease-causing proteins) causes aberrant interaction with the poly-alanine recognizing enzyme of the ubiquitin transfer system. This interaction disrupts the proper ubiquitin transfer to neural proteins, which inhibits the ubiquitous normal functions, leading to cell death and eventually triggering CCHS.  

To make this discovery clinically relevant, the lab used patient-specific stem cells, termed induced pluripotent stem cells (iPSCs). Unlike ESCs, iPSCs are generated without destroying embryos, and can be generated from any individual. The iPSCs from CCHS patients were then differentiated into PHOX2B-expressing cells of the ANS, which revealed the disease mechanism in the most vulnerable of the patient's nerve cells.