The dynamics of dynein diseases
Budding yeast helps researchers examine the mechanisms that link mutations in the gene for the motor protein dynein to diseases in humans.
Motor proteins maintain order by transporting biomolecules and various structures within living cells. Dynein is one such motor that moves many types of cargoes along tracks called microtubules, which are spread across the cell’s interior. This motor is particularly important in nerve cells, which can be very long and thus depend heavily on motor proteins to ensure cargoes end up where they are needed. This becomes especially apparent in human diseases that arise as a consequence of mutations in the genes that produce components of the dynein motor.
It is assumed that these genetic changes simply prevent dynein from working properly, which ultimately affects the health and survival of cells. However, it is currently unknown what specific effect these mutations have on dynein’s role within the cell, and how these changes lead to particular diseases.
Marzo et al. have now used dynein from a budding yeast to closely examine 17 mutations in the dynein gene that are associated with developmental and/or motor neuron diseases in humans. For each mutation, various aspects of how dynein moves (e.g. average speed, distance travelled) were measured and quantitatively compared. The results show that the severity of the effect of each mutation can be directly correlated with the type of disease caused by the mutation. In particular, mutations that lead to less severe defects are found in patients that suffer from various motor neuron diseases, while more severe dynein mutations are found in patients with developmental brain disorders. Marzo et al. confirmed the likely structural changes that caused the defects in dynein’s activity in two of the 17 cases, by engineering additional, restorative mutations that lessened the effects of the primary mutation.
These findings reveal links between the molecular impact of defects in the dynein gene and human health. They also confirm that budding yeast is a powerful tool for investigating newly discovered dynein mutations that correlate with disease. This study provides a potential system that could be used to screen drugs that might lessen the effects of specific dynein mutations. However, further work is needed to determine how effective this system will be for drug discovery.
Originally published at https://elifesciences.org/digests/47246.
