Genetic defects can lead to neurodegenerative diseases, impacting motor control and other vital functions. Researchers at the CECAD Cluster of Excellence in Aging Research and the CEPLAS Cluster of Excellence in Plant Sciences at the University of Cologne are exploring the protective mechanisms of plants to treat neurodegenerative diseases in humans.

By Susanne Kutter

Huntington’s disease, also known by its older name Huntington’s chorea, is rare, but detrimental to those who suffer from it. The hereditary disease is a prime example of a so-called monogenic defect, featuring prominently in many biology textbooks. A single gene is affected by a mutation – with devastating effects: the symptoms of the disease include involuntary twitching movements and a characteristically impaired gait. This is caused by the gradual destruction of nerve cells in areas of the brain that are important for controlling muscles as well as for mental and cognitive functions. 

Another reason for the sad notoriety of this neurodegenerative disease, which is always fatal, is that it serves as a particularly glaring example in the discussion about the pros and cons of genetic testing. Since 1993, the predisposition can be detected genetically. However, it often takes decades for the onset of symptoms, during which those afflicted live in fear of inescapable mental and physical decline – without hope for a cure.

A team of researchers at the CECAD Cluster of Excellence in Aging Research and the CEPLAS Cluster of Excellence in Plant Sciences are pursuing a promising approach to developing a new treatment for Huntington’s disease and other neurodegenerative conditions in humans. In a publication in Nature Aging, Professor Dr David Vilchez, Dr Ernesto Llamas and their colleagues showed that a synthetic enzyme derived from plants can reduce the clumping of proteins at the root of these diseases. The enzyme is not, in the pharmacological sense, a plant substance that can be swallowed as a remedy. Rather, the researchers looked at – and copied – a mechanism that plants use to combat a similar phenomenon that underlies Huntington’s disease and a number of similar neurological conditions.

In all living organisms, genes determine the precise way in which proteins are produced. It is a complex, multi-step process called expression. In Huntington's disease, clumps – so-called aggregations – of a protein called huntingtin are responsible for the death of nerve cells in the brain. The gene defect at the root of the disease causes the protein to be folded incorrectly into its three-dimensional form. As a result, it clumps together and is deposited as a deadly layer on the nerve cells.

Huntingtin – The disease-causing gene defect itself consists of a multiplication of a certain triplet combination of genetic letters, the bases cytosine (C), adenine (A) and guanine (G). This so-called triplet of CAG is translated into the amino acid glutamine (internationally abbreviated as Q) when the genes are read. If the triplet occurs several times – in the most severe forms of the disease up to 60 times – the reading product, the protein huntingtin, becomes unstable.

No problems with protein aggregations

Huntington’s belongs to the so-called polyglutamine diseases, a special group of genetically caused neurological defects. But it is not the only one: nine such diseases have been described so far, all of which are still incurable. What the two scientists found remarkable: these kinds of polyglutamine structures also occur in plants, but do not seem to harm them. Plants express hundreds of proteins containing glutamine repeats, but no pathologies have been found.

Plants are exposed to constant environmental challenges, but cannot move to escape these conditions. Nevertheless – or precisely because of this – they possess a remarkable resistance to stress, enabling them to live long lives. Unlike humans, who suffer from so-called proteinopathies like in Huntington’s disease caused by the toxic aggregation of proteins, these types of diseases do not occur in plants.

The team, which also includes the plant scientist Professor Dr Alga Zuccaro at CEPLAS, wanted to know how a plant would cope with huntingtin, which is mutated and toxic for humans and animal models. To study the effects, they introduced it into the popular model plant Arabidopsis thaliana. By means of gene transfer, they transferred human huntingtin, or more precisely its Q69 fragment, into the plant cells. With a further trick, they ensured that the gene would not only be copied, but overexpressed. Hence, the deadly protein was abundant in the cells of the budding plants. But in contrast to animal models and humans afflicted by the disease, the plant is able to actively remove the huntingtin clumps that formed and thus to avoid the negative effects.  

“We were surprised to see plants completely happy and healthy, even though they were genetically producing the toxic human protein,” said CECAD researcher David Vilchez, who usually works with cell cultures and nematodes as model organisms. The next step was to find out precisely how plants manage to avoid the toxic aggregation of mutated huntingtin. As it turned out, the key lay in the chloroplasts, the plant-specific organelles that carry out photosynthesis and obtain energy from light. Llamas said: “Unlike humans, plants have an extracellular type of organelle available, the chloroplasts, which apparently provides an extended molecular machinery to get rid of toxic protein aggregates.” The multidisciplinary team then identified the chloroplast plant enzyme Stromal Processing Peptidase (SPP) as the decisive protective mechanism that safeguards the plants against the problematic human protein. 

Start-up planned

The team then introduced synthetically produced SPP (or the corresponding gene for it) into animal model organisms. And indeed: the plant SPP reduced protein clumps and symptoms in Huntington’s disease models, for example in cultured human cells and worms like the nematode Caenorhabditis elegans. Dr Hyun Ju Lee, a postdoc involved in the research, said: “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, when the symptoms are even worse.” The results thus open the door to testing SPP as a potential therapy for Huntington’s disease.   
Dr Seda Koyuncu, another postdoc involved in the study, 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.” This hope has now earned the team funding under the GO-Bio initial programme of the German Federal Ministry of Education and Research (BMBF). According to Llamas, the plan is to found a start-up for the production of plant proteins in order to test them as potential therapeutics for the treatment of neurodegenerative diseases in humans.

It is still early to say whether or not plant chloroplasts actually hold the key to successfully treating Huntington’s and other polyglutamine diseases. So far, the researchers also cannot assess what side effects the plant enzyme might have in humans. Many of the therapies tested so far have failed precisely because of this. In the last two years, for example, two global companies (Novartis and Roche) gave up on their originally promising Huntington’s clinical trials because of serious side effects. But this completely new mechanism certainly represents a glimmer of hope.

Ernesto Llamas puts it this way: “We usually forget that some plants can live for thousands of years and should urgently be studied as models for ageing research.” With their collaboration between aging research, including neurodegeneration, and plant science, the researcher team are real trend-setters: a whole series of research projects all over the world are starting to pursue similar approaches.
 

Further Information:
CECAD Cluster of Excellence in Aging Research
Website Prof. Dr. David Vilchez
Read paper on Nature Aging