Plant Chloroplasts Promise Potential Therapy for Huntington’s Disease

Huntington’s disease is among the so-called polyglutamine (polyQ) diseases, a group of neurodegenerative disorders caused by multiple repetitions of glutamine amino acids in specific proteins.  Huntington’s disease is an inherited condition that causes widespread deterioration in the brain and disrupts thinking, behavior, emotion and movement.

In their recent study, Professor Dr David Vilchez (CECAD) and Dr Ernesto Llamas (CEPLAS) followed an unconventional approach to find potential drugs to treat polyQ diseases like Huntington’s. Plants are constantly challenged by the environment, but they cannot move to escape from these conditions. However, plants possess a striking resilience to stress that allows them to live long. Unlike humans who suffer from proteinopathies caused by the toxic aggregation or cluster of proteins, plants do not experience these kinds of diseases. They express hundreds of proteins containing polyQ repeats, but no pathologies from these factors have been reported. To explore how plants deal with toxic protein aggregation, Dr Ernesto Llamas, first author of the study, and colleagues introduced the toxic mutant protein huntingtin in plants, which causes cell death in human neurons.

“We were surprised to see plants completely healthy, even though they were genetically producing the toxic human protein. The expression of mutant huntingtin in other models of research like human cultured cells, mice and nematode worms induce detrimental effects and symptoms of disease,” said David Vilchez.

The next step was to discover how plants avoided the toxic aggregation of mutant huntingtin. Indeed, the scientists discovered that the chloroplasts, the plant-specific organelles that perform photosynthesis, were the reason why plants do not show toxic protein deposits. Llamas said: “Unlike humans, plants have chloroplasts, an extracellular type of organelle that could provide an expanded molecular machinery to get rid of toxic protein aggregates.”

The multidisciplinary team identified the chloroplast plant protein SPP as the reason why plants are unaffected by the problematic human protein. Producing the plant SPP in models of Huntington’s disease such as human cultured cells and worms like the nematode C. elegans reduced protein clumps and symptoms of disease. “We were pleased to observe that expression of the plant SPP protein improved motility of C. elegans worms affected by huntingtin even at later aging stages where the symptoms are even worse,” said Dr Hyun Ju Lee, a postdoc also involved in the study. The results thus open the door to testing SPP as a potential therapy for Huntington’s disease.

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Sources:

Ernesto Llamas, Seda Koyuncu, Hyun Ju Lee, Markus Wehrmann, Ricardo Gutierrez-Garcia, 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 Rodriguez-Concepcion, Alga Zuccaro, David Vilchez. In planta expression of human polyQ-expanded huntingtin fragment reveals mechanisms to prevent disease-related protein aggregation. Nature Aging, 2023; DOI: 10.1038/s43587-023-00502-1

University of Cologne. “Plant chloroplasts promise potential therapy for Huntington’s disease.” ScienceDaily. ScienceDaily, 2 October 2023. <www.sciencedaily.com/releases/2023/10/231002124226.htm>.

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