Modelling the evolution of Parkinson’s from gut to brain
Original article: Transneuronal Propagation of Pathologic a-Synuclein from the Gut to the Brain Models Parkinson’s Disease, Neuron: June 26, 2019.
A new animal model of Parkinson’s has shown that misfolded alpha synuclein injected into the gastrointestinal system can spread from the gut into the brain via the vagus nerve, causing movement and cognitive problems similar to those seen in people with Parkinson’s.
Moreover, severing the vagus nerve or knocking out the alpha synuclein gene in mice protected them from the damaging effects of misfolded alpha synuclein originating in the gut.
Why is it important?
It is a direct test of an important hypothesis and can offer a new way of testing the role of the gut in triggering changes in the brain in Parkinson’s, as well as potential disease modifying therapies.
- Novelty 65% 65%
- Proximity 80% 80%
- Deliverability 80% 80%
“This is potentially a seminal report for the field as it provides a very clear demonstration of gut-to-brain transport of fibrillar alpha synuclein, and the rescue of this phenomenon by vagotomy or genetic ablation. This is not, however, the first time the Braak gut-to-brain theory has been tested and the results of this new study conflict with some previous attempts.
Independent replication will obviously be required, and it will be very interesting if those validation efforts could include a therapeutic approach (such as immunotherapy or anti-aggregating drugs) to test if this spreading of the toxic protein can be halted.”
The possibility that Parkinson’s may begin in the gut and spread into the brain through the vagus nerve was proposed in the early 2000s based on post mortem findings. The vagus (or vagrant, wandering traveler) is the major nerve through which the brain controls many organs of the body including the gut, heart and lungs.
In a new research report, researchers aimed to track the spread of alpha synuclein, the main protein which misfolds in Parkinson’s causing damage to neurons, and address its effects on the brain, as well as on movement and cognition in mice.
Alpha synuclein is normally found in neurons, particularly at synapses. When it misfolds, it begins to cause damage. To directly test the gut to brain hypothesis, the researchers injected misfolded alpha synuclein fibrils directly into the muscular wall of the gut in mice, at the point where the stomach empties into the first part of the small intestine, called the duodenum. These fibrils began interacting with the alpha synuclein found in local nerves in the gut, triggering a further misfolding process.
One month later, the researchers found misfolded alpha synuclein in the brain, specifically at the point at which the vagus nerve originates. Within 3 months, misfolded alpha synuclein could be found in other parts of the brain, including the substantia nigra, the main dopamine centre which is involved in movement, and by 7 months, alpha synuclein could clearly be seen in this region.
The team then addressed the effects of cutting the vagus nerve in mice that had been injected with preformed alpha synuclein fibrils. In comparison to mice with an intact vagus, which had a profound loss dopamine, mimicking what is seen in Parkinson’s, the vagotomised mice were completely protected from this.
Similarly, mice with no gene for alpha synuclein (by genetic knock out, so they did not produce alpha synuclein), were also spared from the damaging effect of fibrils gaining access to the brain through the vagus.
Importantly, in this animal model of Parkinson’s, the animals had problems both in movement as well as cognition, for example in spatial memory and object recognition. They also showed behaviours indicative of anxiety and depression in tests used to assess these psychological states in mice, such as open field settings. The vagotomised and knock out mice were protected from these problems.
As with all research findings, replication will be important. The next steps include understanding what triggers alpha synuclein to misfold in the first place, and how these early events may differ between individuals.
Podcast summary recording
Original article: Kim S, Kwon SH, Kam TI, Dawson VL, Dawson TM, Ko HS. June 26, 2019. Transneuronal Propagation of Pathologic a-Synuclein from the Gut to the Brain Models Parkinson’s Disease