In planta expression of human polyQ-expanded huntingtin fragment reveals mechanisms to prevent disease-related protein aggregation
Ernesto Llamas, Seda Koyuncu, Hyun Ju Lee, Markus Wehrmann, Ricardo Gutiérrez-García, Nick Dunken, Nyasha Charura, Salvador Torres‐Montilla, Elena Schlimgen, Amrei M. Mandel, Erik Boelen Theile, Jan Großbach, Prerana Wagle, Jan‐Wilm Lackmann, Bernhard Schermer, Thomas Benzing, Andreas Beyer, Pablo Pulido, Manuel Rodrı́guez-Concepción, Alga Zuccaro, David Vı́lchez
Abstract
In humans, aggregation of polyglutamine repeat (polyQ) proteins causes disorders such as Huntington's disease. Although plants express hundreds of polyQ-containing proteins, no pathologies arising from polyQ aggregation have been reported. To investigate this phenomenon, we expressed an aggregation-prone fragment of human huntingtin (HTT) with an expanded polyQ stretch (Q69) in Arabidopsis thaliana plants. In contrast to animal models, we find that Arabidopsis sp. suppresses Q69 aggregation through chloroplast proteostasis. Inhibition of chloroplast proteostasis diminishes the capacity of plants to prevent cytosolic Q69 aggregation. Moreover, endogenous polyQ-containing proteins also aggregate on chloroplast dysfunction. We find that Q69 interacts with the chloroplast stromal processing peptidase (SPP). Synthetic Arabidopsis SPP prevents polyQ-expanded HTT aggregation in human cells. Likewise, ectopic SPP expression in Caenorhabditis elegans reduces neuronal Q67 aggregation and subsequent neurotoxicity. Our findings suggest that synthetic plant proteins, such as SPP, hold therapeutic potential for polyQ disorders and other age-related diseases involving protein aggregation.