Huntington’s Aggregates May Be Prevented by Chloroplast Enzyme

Researchers at the University of Cologne’s CECAD Cluster of Excellence for Aging Research and the CEPLAS Cluster of Excellence for Plant Sciences have discovered a promising synthetic plant biology-based approach for the treatment of human neurodegenerative diseases, and in particular Huntington’s disease. The new research showed that a synthetic enzyme derived from plants—stromal processing peptidase (SPP)—reduced the clumping of the polyglutamine repeat (polyQ) proteins that are linked to the pathological changes in models of Huntington’s disease in human cells and the nematode model organism Caenorhabditis elegans.

Reporting on their work in Nature Aging “In planta expression of human polyQ-expanded huntingtin fragment reveals mechanisms to prevent disease-related protein aggregation,” the team concluded, “Our findings suggest that synthetic plant proteins, such as SPP, hold therapeutic potential for polyQ disorders and other age-related diseases involving protein aggregation.”

Huntington’s disease is among the a group of polyglutamine (polyQ) neurodegenerative diseases that are caused by multiple repetitions of glutamine amino acids in specific proteins. An excessive number of polyQ repeats can cause proteins to aggregate or accumulate in harmful and damaging protein deposits, leading to cellular dysfunction and death. To date, nine polyQ disorders have been described in humans. They all remain incurable. Among them, Huntington’s disease is an inherited condition that causes widespread deterioration in the brain and disrupts thinking, behavior, emotion and movement. In their newly reported study, David Vilchez, PhD, at CECAD, and Ernesto Llamas, PhD, at CEPLAS, took an unconventional approach to find potential drugs that might treat polyQ diseases such as Huntington’s.

Plants are constantly challenged by the environment, and while they cannot move to escape from these conditions, they do 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. And, as the team noted, “To our knowledge, unlike mammals, plants do not experience proteinopathies caused by the abnormal aggregation of polyQ proteins … Although plants express hundreds of proteins containing polyQ regions, no pathologies arising from these proteins have been reported to date.” To explore how plants deal with toxic protein aggregation, first author Llamas and colleagues introduced the toxic mutant protein huntingtin—which causes cell death in human neurons—into plants. In contrast to the effects of the mutant huntingtin in animal and human models, they found that Arabidopsis thaliana plants actively removed huntingtin protein clumps and so avoided harmful effects.

“We were surprised to see plants completely healthy, even though they were genetically producing the toxic human protein,” said Vilchez. “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.”

The next step was to discover how plants avoided the toxic aggregation of mutant huntingtin. The multidisciplinary team’s research discovered that chloroplasts, the plant-specific organelles that perform photosynthesis, were the critical factor in why plants do not show toxic protein deposits. “… we expressed an aggregation-prone fragment of human huntingtin (HTT) with an expanded polyQ stretch (Q69) in Arabidopsis thaliana plants,” the authors wrote. “In contrast to animal models, we find that Arabidopsis sp. suppresses Q69 aggregation through chloroplast proteostasis.

The identified the chloroplast protein SPP (stromal processing peptidase) as key to ability of plants to remain unaffected by the problematic human protein. 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.”

Producing the plant SPP in human cell and C. elegans models of Huntington’s disease reduced protein clumps and symptoms of disease. “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,” the investigators stated. “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 co-author Hyun Ju Lee, PhD.

The results could lead to the potential development of SPP as a candidate therapy for Huntington’s disease. “These findings open up an avenue for the discovery of therapeutic, plant-based synthetic proteins that could target human polyQ diseases,” the scientists stated. They acknowledged the need for further research to define the molecular mechanisms by which SPP prevents aggregation of polyQ-expanded proteins, and noted that the potential for off-target effects should also be investigated. Nevertheless, they wrote, “…  it will be fascinating to explore whether synthetic SPP, or other plant proteins, can also prevent aggregation of distinct disease-related proteins … Beyond SPP, our interactome data of polyQ-expanded proteins in plants provide a plethora of potential therapeutic targets that can be explored in future studies.”

Llamas is convinced that plant research can make a meaningful contribution to treating human diseases. “Many people don’t notice that plants can persist amongst variable and extreme environmental conditions that cause protein aggregation. I believe that plant molecular mechanisms hold the key to discovering new drugs that can prevent human diseases. We usually forget that some plants can live thousands of years and should be studied as models of aging research.” Co-author Seda Koyuncu, PhD, added, “Over the past years we have seen several promising approaches to treating hereditary diseases like Huntington’s fail. We are confident that our plant synthetic approach will lead to significant advances in the field.”

The team has since acquired funding form the German Federal Ministry of Education and Research through the GO-Bio initial program. “We want to bring our idea into an application,” Llamas said.” Our plan is to found a start-up to produce plant-derived therapeutic proteins and to test them as potential therapeutics to treat neurodegenerative diseases in humans.”

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