The diagnosis of Parkinson’s disease is based on significant motoric symptoms like trembling, decreased movements, and stiffness. This has been attributed to the death of neurons that produce the neurotransmitter dopamine. However, the disease may often start much earlier with diffuse symptoms like depression, sleep disturbances, and constipation. Symptoms that are not associated with death but are more likely dysfunction of neurons. Now a new collaboration of researchers is changing the perspective of the last 20 years of research from focusing on the death of neurons to the preliminary dysfunctions of the neurons.
One is an expert in the protein alpha-synuclein, which when aggregating contributes to nerve cell dysfunction and death, another is a specialist in the nerve ending where the initial aggregation occurs, and the third, in the cells’ “cleaning system” for abnormal protein aggregates – together they form a new neuroscience “dream team” covering the most defining molecular mechanisms of the functional decline of brains affected by Parkinson’s disease.
Assistant Professor Dr. Marijn Kuijpers from the Donders Institute for Brain, Cognition, and Behavior at Radboud University, Professor Fulvio Reggiori, and Professor Poul Henning Jensen, both from the Department of Biomedicine at Aarhus University have joined the forces of their respective labs to change the perspective of the last 20 years of research in Parkinson’s disease:
“Scientifically, we are a very complementary team. I contribute my expertise in Parkinson’s disease, alpha-synuclein pathophysiology, and its modeling. Marijn brings in advanced neurobiological tools and expertise on cellular neuroscience in general and axonal, synaptic, and endoplasmic reticulum biology in particular. Fulvio is an established expert in cellular protein degradation with a focus on autophagy and its general ability to degrade aggregated proteins. Together, this allows us to conduct a very detailed study of the early Parkinson’s disease-related mechanisms that we hypothesize initiates in nerve terminals before spreading via axons to the cell bodies,” Professor Poul Henning Jensen explains.
Exploring the stage before cell death
Our focus is on the early changes occurring in nerve terminals and axons before bulky alpha-synuclein aggregates accumulate as easily detectable “garbage” in neurons. This is rather unique and holds potential because they may represent important contributors to a range of the patients’ symptoms. This early part of the physiologic process has never been studied in depth before as a part of the development of neurodegenerative diseases:
“The primary focus of the last 20 years of research has been on the big aggregates in the cell body, and the phase when the cells start to die, which we hypothesize is a tertiary phase. We hypothesize there exist two preceding phases where small aggregates create havoc in the nerve terminals and axons that disturbs neurotransmission causing symptoms. Such a dysfunctional phase may last for many years, and here the cells are struggling to keep up, but far from dying,” says Poul Henning Jensen.
He mentions as an example the visual disturbances and hallucinations that often accompany diseases like Lewy Body dementia and Parkinson’s disease. These symptoms stem from the cortical areas in the back of the brain, but according to Poul Henning, there is no significant cell death occurring in these areas, which means the molecular basis for these symptoms has not been addressed hitherto. This is exactly what the new collaboration wants to change.
“Now recent data suggest that there actually exists synuclein-aggregates in this area, but they do not condense into these Lewy Bodies. Based on the previous scoring of Parkinson’s disease pathology, these cells have not been considered “sick”. We hypothesize these poorly detectable aggregates in axons in nerve terminals are key contributors to the disease progression and symptomatology. These contributions are partly mediated by changes in ion fluxes that may be targeted for therapeutic intervention. If our hypothesis is true, this could have a great impact on the quality of life for these patients”.
Besides the three core members, the collaboration will also include the collaborators from the Department of Biomedicine and DANDRITE at Aarhus University and Aarhus University Hospital in Skejby, that are experts in mitochondria, proteomics, transcriptomics, electron microscopy, and in-vivo-modeling respectively. Combined, this makes it possible to model the different phases of the aggregate-dependent changes to nerve cells at an extremely detailed level, which has not yet been possible with conventional methodologies.
By mapping each step of the nerve cells’ slowly progressive deterioration, the collaborators hope to identify tractable intervention points in the disease-associated signaling pathways.
“We will know a lot more about what happens in a nerve cell when synuclein starts to aggregate and slowly accumulate in specific sites in neurons. Our goal is to both help the cells clean up their “garbage”, and to reset to the abnormal aggregate-induced signaling pathways,” Poul Henning explains.
“Together we can really reach far”
The new collaboration has become a reality because of a generous grant of 20 million DKK from the Lundbeck Foundation, the so-called “LF Collaborative Projects”. The grant aims to spur cutting-edge research by combining different disciplines. According to Poul Henning Jensen, the collaborative aspect is exactly what is needed to push the research forward:
“I think research is a very selfish business. We all hopefully work on something that we find exciting and compete to get as far as possible. But you can’t be good at everything, so it's very important to work with other specialists in the field because they can help you answer questions you were not able to answer yourself and pose questions that you are not aware you could or should ask. Together we can really reach far,” Poul Henning argues.
The project will run for the next five years and will build upon a previous five-year research project that constitutes a strong foundation for believing in a future breakthrough in this research field. At least according to Poul Henning Jensen who has more than 25 years of experience in the research of Parkinson’s:
“We have very exciting preliminary data that suggests that what we are working on may actually bring something novel. And, if we can be as successful in patients as we are in animals, we have reasons for really high expectations”.