Euan MacDonald Centre researcher Professor Cathy Abbott and her former PhD student Lowri Griffiths, with colleagues from the NYU Langone Medical Centre and elsewhere, have uncovered the mechanisms by which cells continue to function normally under conditions of stress. At the same time, the work provides new insights into why motor neurons might be particularly vulnerable to cellular stress.
Heat shock proteins protect the molecules in all human and animal cells with factors that regulate their production and work as thermostats.
The new research, published on 16th September in the journal eLife, reports for the first time that a protein called translation elongation factor eEF1A1 orchestrates the entire process of the heat shock response. By doing so, eEF1A1 maintains the correct protein balance in cells in various internal and external stress conditions.
In neurodegenerative diseases such as MND, the nerve cells lack enough protective heat-shock proteins to insulate them from protein-damaging stress. Restoring the heat shock response to its full capacity could potentially avoid or halt progression of MND and other conditions such as Alzheimer’s or Parkinson’s disease and even cancer.
“It’s a bit early, but we think that eventually we could design small-molecule activators and inhibitors that tweak the heat shock response,” says Evgeny Nudler, PhD, the study’s senior investigator at NYU Langone. “eEF1A1 controls every single step of the heat shock response simultaneously.”
The eEF1A protein is expressed in two similar forms, 1 and 2, in different tissues. Interestingly, motor neurons express form 2 (eEF1A2), which does not support the heat shock response. This might be why these specialised cells cannot mount the heat shock response and therefore are particularly vulnerable to stress and diseases such as MND.
The challenge in drug development will be restoring the heat shock response in motor neurons by modulating the activity of eEF1A.