DZNE scientists are being funded with 541,000 euro as members of an international research network on Parkinson’s, which is supported by the European Union, the European Federation of Pharmaceutical Invdustries and Associations and Parkinson’s UK, a British patient advocacy organization. The consortium, termed PD-MitoQUANT, will study disease mechanisms, in particular the role of mitochondrial dysfunction. We talked to Donato Di Monte, a senior researcher at the DZNE’s Bonn site, about this scientific endeavor.
Dr. Di Monte, the project focus is on mitochondria. What are mitochondria?
Mitochondria are the cell’s powerhouses. They are small compartments within the cells where a molecule called ATP is produced. ATP is very rich in energy and serves as a cellular fuel.
Where do mitochondria occur?
Mitochondria occur in every cell, as every cell needs energy. However, mitochondria are particularly important for cells in the brain and in the muscles, because neurons and muscle cells require a lot of energy.
This project aims to find new approaches to fight Parkinson’s disease. Why does it focus on mitochondria?
Parkinson’s disease is associated with the death of neurons in specific regions of the brain, particularly in an area called the “substantia nigra”. The affected neurons normally produce the neurotransmitter dopamine, which is essential for movement control. As these neurons die, levels of dopamine fall. Consequently, people with Parkinson’s suffer from movement disorders such as tremor and stiffness of their arms and legs. The question is: What causes these neurons to die? There is evidence that mitochondrial dysfunction is likely to be involved. This evidence comes from various studies and observations. To give one example, in the 1980’s, individuals who injected themselves with a batch of an illicitly synthesized drug developed symptoms of Parkinson’s. As it turned out, this drug contained a substance called MPTP. MPTP is a mitochondrial poison and specifically kills neurons in the substantia nigra, thus suggesting a high vulnerability of these neurons to mitochondrial dysfunction. Other observations, including the observation of mitochondrial impairments in the brain of patients, point to the same direction, substantiating the idea that mitochondria defects could play a key role in the development of Parkinson’s disease.
What about the so-called “Lewy bodies”, which accumulate in the brains of people with Parkinson’s? What is their role in this disease?
Lewy bodies are abnormal clumps of proteins that are formed within neurons in the brain of patients. Their major component is a protein called “alpha-synuclein”. The relationship between alpha-synuclein aggregation and Lewy bodies was discovered in the late 1990’s and, since then, there has been a lot of research on how alpha-synuclein could cause or contribute to Parkinson’s. Despite all these efforts, we still don’t fully understand the role of alpha-synuclein in Parkinson’s. In particular, we do not know if there is a relationship between this protein and mitochondrial dysfunction. This is exactly where the current research project comes in. We want to investigate if there is a link between mitochondrial abnormalities, alpha-synuclein aggregation and, ultimately, neuronal degeneration. If such a link is found, this would have important implications for our understanding of how Parkinson’s develops and could pave the way for the development of new therapies targeting specific interactions between alpha-synuclein and mitochondria. Parkinson’s has a progressive pathology, meaning that the symptoms of the disease get worse over time. Current therapies can mitigate some of symptoms of Parkinson’s but cannot stop the disease from progressing. Therefore, finding a treatment that slows or even halts this progression is a critical need and a major focus of PD-MitoQUANT.
What is known about alpha-synuclein under healthy conditions?
Alpha-synuclein is a synaptic protein, meaning that it is abundant at the level of neuronal synapses. Synapses are where neurons communicate with each other, and there is evidence that alpha-synuclein plays a role in signal transmission between neurons. It may also be important for synaptic plasticity, which refers to the adaptability of synapses. This adaptability is important for brain functions such as learning and memory. Even before alpha-synuclein was identified as a protein associated to Parkinson’s, an intriguing information concerning its function came from studies in songbirds. When these birds learn how to sing, levels of alpha-synuclein rise up in their brains. This could be related to synaptic plasticity. Alpha-synuclein could be involved in these mechanisms during brain development as well as during the continuous re-adaptation of synapses throughout life.
But then, why would alpha-synuclein be harmful?
Similar to other proteins involved in pathological processes, alpha-synuclein seems to have a kind of a schizoid behavior, like Dr. Jekyll and Mr. Hyde. Unfortunately, however, we don't know as yet the switch (or switches) that turn alpha-synuclein from being a “good guy” into becoming a “bad guy”. But there are some clues. One of the switches is simply an increased concentration of this protein within neuronal cells. How do we know this? Well, there are individuals that carry mutations with multiple copies of the alpha-synuclein gene. These individuals have the same normal alpha-synuclein as everybody else; the only difference is that they have more of it. And this is enough to develop symptoms of Parkinson’s. So, we clearly know that having more alpha-synuclein than normal causes a significant neuronal burden. But certainly there are other switches that could make alpha-synuclein pathological. It could be anything that would promote, for example, alpha-synuclein aggregation as it is observed within Lewy bodies. Another potential switch may be represented by alpha-synuclein interactions with mitochondria.
How could this interaction look like?
As both mitochondria and alpha-synuclein are present at the synapses, there is certainly a chance for them to interact. What could be the consequence? One possibility is that alpha-synuclein promotes the generation of reactive oxygen species by mitochondria. Reactive oxygen species are generated during the physiological process of mitochondrial ATP production. Cells (including neurons) can normally cope with this “side-effect” of energy metabolism. However, if the generation of these reactive species is enhanced, then a condition called “oxidative stress” may arise and could ultimately be harmful to the cells. Alpha-synuclein, especially in its aggregated forms, can increase the mitochondrial production of reactive oxygen species. In turn, reactive oxygen species may promote alpha-synuclein’s tendency to aggregate. As a result, a kind of a vicious cycle may be triggered, leading to the accumulation of pathological alpha-synuclein, decrease functionality of mitochondria and ultimately neuronal demise. Although supported by initial evidence, this remains a working hypothesis. This as well as other hypotheses will be fully tested as part of the PD-MitoQUANT project. We also expect that the project will generate new, perhaps unexpected data, opening research avenues that go beyond our current knowledge and current hypotheses.
What will be the DZNE’s contribution to the project?
The consortium is really multidisciplinary. The idea is to do experiments on all fronts. Each member of the consortium contributes its own expertise and, at the same time, experiments will often be conducted at different sites to verify reproducibility. Within the consortium, different experimental models and technologies such as high-resolution imaging and computer modelling will be used. The project does not include clinical trials with patients. However, cells derived from individuals with alpha-synuclein mutations will be studied. The expectation is that, by bringing together all this expertise and state-of-the art technology, we will identify and validate mechanisms of mitochondria-alpha-synuclein interactions that could become targets for the development of new drugs. As far as studies that will specifically be carried out at the DZNE, our role stems from our long-lasting experience in reproducing key pathological aspects of Parkinson’s disease in the laboratory setting using complex organisms. In particular, we will mimic alpha-synuclein aggregation and induce the degeneration of dopamine-containing cells to establish their relationship with mitochondrial dysfunction and changes in mitochondrial morphology. A variety of biochemical assays and imaging techniques are available here for these purposes. The latter will allow, for example, zooming in and evaluating mitochondrial changes at the cellular level in specific brain regions.
The different teams are distributed throughout Europe. How will they interact?
Recently, we had a kick-off meeting in Dublin with representatives of all teams from nine different countries. During the meeting we discussed detailed plans to share resources, conduct parallel work using different experimental models at different sites, and to implement a rigorous collection and evaluation of data. We also established smaller working groups focusing on specific components of the research project. Judging from this first meeting, a major strength of PD-MitoQUANT is the dynamic interaction among members of this consortium. From now on, we will continue to be in touch regularly on a monthly basis through mailings and conference calls.
Parkinson’s is a neurodegenerative disease that manifests through movement disorders and other health issues. Current treatments only have a symptomatic effect. PD-MitoQUANT is intended to break ground for better therapies. The project will run for three years, involving 14 partners from nine countries, both form academia and industry. PD-MitoQUANT is a research project of the “Innovative Medicines Initiative”, a public-private partnership between the European Union and the European Federation of Pharmaceutical Industries and Associations (EFPIA). As such PD-MitoQUANT is receiving 4.5 million euro in funding from the EU’s Horizon 2020 programme and 2.46 million euro in-kind from EFPIA members and Parkinson’s UK, a British patient advocacy organization.