Understanding How Plants Eliminate Protein Folding Could Help with ALS Research
In some neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), nerve cells fold their proteins incorrectly, leading to cell death. Using plants, researchers discovered that when defective proteins accumulate in chloroplasts – a plant’s cellular compartment where photosynthesis occurs – it generates a distress signal that produces reparative proteins to correct the problematic ones.
Scientists from the Center for Research in Agricultural Genomics (CRAG) in Barcelona, Spain, found that this “Mayday” signal is dependent on the activation of the HsfA2 gene.
Their work, “Interference with plastome gene expression and Clp protease activity in Arabidopsis triggers a chloroplast unfolded protein response to restore protein homeostasis,” was published in Plos Genetics.
Both animals and plants are dependent on proteins to keep their cells alive. To function properly, proteins are folded into a three-dimensional configuration. If they fail to fold correctly, the proteins will be unable to function. These misfolded proteins can form toxic aggregates and must be removed or repaired to avoid potential cell death.
Chloroplasts are the cellular compartments responsible for plant cell photosynthesis and produce many of the nutrients for plant and animal growth (when animals ingest plants).
Defective protein folding causes nervous system diseases in humans, including ALS and Parkinson’s disease, and in plants, it compromises chloroplast function.
Using the model plant Arabidopsis thaliana, the CRAG team found that chloroplasts eliminate the defective proteins with an enzyme called protease Clp.
When Clp fails, defective proteins accumulate. In an emergency “cell salvation” response, chloroplasts generate a distress signal that travels to the nucleus of a plant’s cell. This causes the activation of the HsfA2 gene, which in turn leads to the production of reparative proteins known as chaperones. These chaperones are transported to the chloroplasts, where they unfold and eliminate protein aggregates.
“The signaling pathway from the chloroplasts to the nucleus turns on a molecular switch called HsfA2. This key gene is also activated when a heat stroke causes problems of protein folding in other cellular compartments,” Ernesto Llamas, the first author of the study, said in a press release.
Ultimately, chaperones allow proteins to be folded back correctly and become fully operational in a matter of hours, rescuing cells from the toxic effects of defective proteins.
This discovery could shed light on how neurodegenerative diseases associated with protein misfolding start, spread, and worsen. It could also lead to new insight into how to correct protein misfolding, which would contribute to a possible cure for these currently incurable diseases.