In planta expression of human polyQ-expanded huntingtin fragment reveals mechanisms to prevent disease-related protein aggregation

Author:

Llamas ErnestoORCID,Koyuncu Seda,Lee Hyun Ju,Wehrmann MarkusORCID,Gutierrez-Garcia Ricardo,Dunken Nick,Charura Nyasha,Torres-Montilla Salvador,Schlimgen Elena,Mandel Amrei M.ORCID,Theile Erik Boelen,Grossbach Jan,Wagle Prerana,Lackmann Jan-WilmORCID,Schermer Bernhard,Benzing Thomas,Beyer AndreasORCID,Pulido PabloORCID,Rodriguez-Concepcion Manuel,Zuccaro Alga,Vilchez DavidORCID

Abstract

AbstractIn 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.

Publisher

Springer Science and Business Media LLC

Subject

Neuroscience (miscellaneous),Geriatrics and Gerontology,Aging

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