New Studies Support a Critical Role for Alpha Synuclein in PD
At the WPC 2019 in Kyoto, I was invited to give a Hot Topics lecture and to be part of the Poster Tour program to allow me to further discuss the work of my team with other delegates. Since that great event, we have published in May 2020 the two papers that were presented at WPC 2019.
The basic problem in Parkinson's disease (PD) is loss of dopamine-producing nerve cells in a region of the brain called the substantia nigra pars compacta (SNc). Everybody has a gradual loss of these dopamine-producing nerve cells as they age, but PD patients have lost more of them than other people. Why these cells die in PD is unclear, and the focus of much research. To answer these questions, research requires the use of a variety of animal models to study different aspects of the disease. An international group of German (B. Mollenhauer), qatari (O. El Agnaf), Spanish (M. Vila, MT Herrero, J Obeso) and French (P. Derkinderen, B. Dehay, E. Bezard) senior researchers teamed up to address fundamental questions regarding development of synucleopathies in non-human primates, a species which brain anatomy and physiology is close enough to human beings to allow direct translation.
In the first study published in May 2020 in Science Advances, we show that dopaminergic neurodegeneration can be induced in non-human primates by both, small and large aggregates of a-synuclein. In contrast, experiments in rodents, used in 85% of studies, show that small a -synuclein aggregates do not induce neurodegeneration.
The so-called protein, a -synuclein, has a central role in the development of PD. In 2014, we had showed that pathological forms of the a-synuclein protein present in the brain of deceased PD patients were capable of initiating a Parkinsonian-like pathological process in mice and primates. Using the same human aggregates, we now characterized the synucleinopathy in non-human primates, by comparing these human aggregates with fractions containing soluble and smaller a-synuclein aggregates. To our biggest surprise, while these small a-synuclein aggregates did not produce any neuronal cell death in mice, non-human primates showed neurodegeneration after small aggregates injection; to the same extent of big aggregates (Fig. 1). These findings provide new information on how the disease is initiated and amplified, and shows that, in non-human primates, a small amount of singular a-synuclein aggregates is as toxic as larger amyloid fibrils, reinforcing the need for preclinical research in non-human primates. These results have dramatic impact upon search for disease modifying therapies as focusing upon rodent species only in our therapy development programs may simply ignore the diversity of synucleopathy-causing mechanisms.
The origin of misfolding trigger signal of a-synuclein remains a mystery. The research about the gut-brain axis emerged in 2003 when a neuroanatomists team led by Heiko Braak spotted a-synuclein inclusions within the enteric nervous system of people who had died with PD. They proposed a staging scheme in which α-synuclein pathology spread from the gut to the brain. However, the intestinal origin of PD has not been proved in nonhuman primates and the bidirectional travel of a-synuclein is still under investigation.
We (the international team) included that key question into our thorough investigations and have found additional evidence that brain alpha-synuclein can also travels down to the gut. The study, described in the May 2020 issue of Brain, offers a new invaluable primate data exploring the role of the gut-brain axis in the initiation and propagation of PD pathology.
We now show that extracted α-synuclein aggregates of brains of dead patients have the ability to initiate and extend the neurodegenerative process that typifies PD in mice and primates. Using the same human aggregates, this study shows that, not only α-synuclein spreads from the gut to the brain, but also travels from the brain to the gut. Understanding how the disease develops over time should open the door to the development and testing of new therapeutic approaches.
Although further experiments are necessary, the study also suggests that the transmission of α-synuclein pathology does not go through the vagus nerve as it was previously suggested. Instead, the results suggest a possible systemic mechanism, in which the general circulation would act as a route for long-distance bidirectional transmission of endogenous α-synuclein, strengthening the predictive role of a-synuclein as a biomarker.
The two papers are the first outcome of a large project including many international laboratories and WPC was the perfect platform to present these data which are now available to everyone, thanks to their publication in high profile journals. We are eager to come to WPC 2022 to present the next generation of ground-breaking data our consortium will likely produce by then.
You may view the interview here:
Dr. Erwan Bezard, PhD is the Director of Institute of Neurodegenerative Diseases at the University of Bordeaux, France.
This research was first shared as an abstract at the WPC 2019 in Kyoto. WPC is pleased to support abstract authors by sharing their ongoing work. Digital files of WPC abstract books can be downloaded from the past three Congresses HERE.
Ideas and opinions expressed in this post reflect that of the author(s) solely. They do not necessarily reflect the opinions of the World Parkinson Coalition®