Molecular motor clue to rare genetic disorder
Chaperone protein could provide new therapeutic avenue for primary ciliary dyskinesia
Primary Ciliary Dyskinesia (PCD) is a rare genetic disorder, affecting approximately 1:15,000 live births which causes respiratory distress in newborns, recurrent airway infections in infants, chronic lung disease and infertility. Although nearly 40 different genes have been linked to PCD, we still lack effective treatment for this debilitating condition. We know that PCD arises due to faults in cilia, which are hundreds of hair-like projections on the cells that make up our body. Healthy cilia can move and brush out mucus and clear pathogens from the lungs. This movement is possible when multiple proteins come together to form molecular motors called dyneins. In cells, these molecular motors are assembled, using a very complex process, on a huge scale. Understanding how individual pieces, or subunits, of the dyneins come together into the right complexes and pass functional quality control tests is important because defective dyneins can lead to PCD, a severe human disease.
Dr Pleasantine Mill, at the MRC Human Genetics Unit, University of Edinburgh, and colleagues have identified a new disease mechanism at the heart of PCD. A protein called ZMYND10 helps chaperone the specialised dynein motors which power sperm tails and motile cilia during their multi-step assembly. Without this protein chaperone as a quality control mechanisms, dynein motors are not properly built and eventually get cleared out to protect the cell.
It is possible that drugs which might help bypass the quality control tests during dynein motor assembly or mimic the roles of ZMYND10 in its absence could provide a therapy for PCD by preventing the motors from becoming defective and being destroyed by the cell. Making dynein motors functional again could have a real impact on the quality of life of PCD patients.
Original research paper: https://doi.org/10.7554/eLife.34389