Ernesto Llamas smiling as he sits at the lab bench with Arabidopsis plants.
Ernesto Llamas, a plant biologist at the University of Cologne, studies how Arabidopsis thaliana plants actively remove harmful protein aggregates and avoid their harmful effects.
Jenny Fenger

Plants and humans are different in many ways, but they share some commonalities. For instance, plants express hundreds of proteins containing polyglutamine (polyQ) regions.¹ Humans express similar proteins, but in humans their buildup causes neurodegenerative diseases like Huntington’s disease. Understanding plants' survival holds therapeutic promise for protein aggregation related diseases, according to Ernesto Llamas, a molecular biologist at the University of Cologne. 

Llamas and his team sought to identify the mechanism that renders plants immune to toxic protein aggregation. In a paper published in Nature Aging, Llamas described a chloroplast protein that shields plants from the harmful effects of polyQ proteins.² His findings hint at the use of chloroplast proteins as unconventional future therapies for polyQ diseases. 

Llamas grew genetically modified Arabidopsis thaliana plants to express low (28 glutamine) and high (69 glutamine) repeat levels of human huntingtin protein, where greater than 35 glutamine repeats trigger polyQ aggregation. Llamas expected to see aggregates, but to his surprise, the plants developed normally. 

“Plants have a principal characteristic: chloroplasts,” said Llamas. “This extra organelle contains expanded molecular machinery to deal with toxic protein aggregates.”

When he analyzed plant-human protein interactions, one caught his eye: polyQ proteins bound to a chloroplast-specific protein called stromal processing peptidase (SPP). Chloroplasts imported and degraded polyQ proteins; when the team disrupted the chloroplasts, this clean-up machinery ceased.

Llamas wanted to transfer SPP’s protective ability to human cells. He cotransfected human cells to overexpress polyQ containing proteins and to express SPP. Microscopy and protein measurements showed that SPP reduced protein aggregation compared to cells with polyQ aggregation that did not express SPP.

“It is a big discovery to express plant SPP in their experimental models,” said Piere Rodriguez Aliaga, a biophysicist at Stanford University who was not involved in the study. “The therapeutic effect is there, but the off-target effects [with other proteins] are still a puzzle that needs to be solved.”

Moving forward, Llamas is optimistic about the therapeutic potential of harnessing the protective power of chloroplasts.

References

  1. Kottenhagen N, et al. Proc. GCB. 2012;26:93-107.
  2. Llamas E, et al. Nat Aging. 2023;3:1345-1357.