A theory that Parkinson’s disease can arise in the intestinal system and from there migrate to the brain has now gained support from new research[1]. Aarhus University investigators observed the disease migrate from the gut to the brain and heart of laboratory rats.

Parkinson’s disease is characterised by slowly destroying the brain due to the accumulation of the protein alpha-synuclein and the subsequent damage to nerve cells. The disease leads to shaking, muscle stiffness, and characteristic slow movements of sufferers.

In the new research project, the researchers used genetically modified laboratory rats which over-express large amounts of the alpha-synuclein protein. These rats have an increased propensity to accumulate harmful varieties of alpha-synuclein protein and to develop symptoms similar to those seen in Parkinson’s patients.

Parasympathetic And Sympathetic Pathways

The researchers started the process by injecting alpha-synuclein into the small intestines of the rats. According to professor Per Borghammer and postdoc Nathalie Van Den Berge, the experiment was meant to demonstrate that the protein would subsequently spread in a predictable fashion to the brain.

“After two months, we saw that the alpha-synuclein had travelled to the brain via the peripheral nerves with involvement of precisely those structures known to be affected in connection with Parkinson’s disease in humans. After four months, the magnitude of the pathology was even greater. It was actually pretty striking to see how quickly it happened,"

says Per Borghammer, who is professor at the Department of Clinical Medicine at Aarhus University.

[caption id=“attachment_99959” align=“aligncenter” width=“700”]Schematic overview of the hypothesized trans-synaptic bidirectional propagation of asyn pathology through the autonomic nervous system to the brain after gastrointestinal seeding. Schematic overview of the hypothesized trans-synaptic bidirectional propagation of asyn pathology through the autonomic nervous system to the brain after gastrointestinal seeding.
Credit: Nathalie Van Den Berge et al. CC-BY[/caption]

Both Parkinson’s and Lewy Body Dementia may be caused by a malfunction in the processing of glucose in mitochondria. This malfunction produces free radicals that damage neighboring molecules and systems that lead to the alpha-synuclein protein clusters that are associated with Parkinson’s and LBD.

These misfolded proteins also cause havoc in cells through a number of different mechanisms, including mitochondrial dysregulation, toxic gain and loss of functions, general cellular dysregulation, and loss of proteasome function.

Twenty Years Before Diagnosis

Per Borghammer explains that patients with Parkinson’s disease often already have significant damage to their nervous system at the time of diagnosis, but that it is actually possible to detect pathological alpha-synuclein in the gut up to twenty years before diagnosis[2].

“With this new study, we’ve uncovered exactly how the disease is likely to spread from the intestines of people. We probably cannot develop effective medical treatments that halts the disease without knowing where it starts and how it spreads — so this is an important step in our research,"

says Per Borghammer.

“Parkinson’s is a complex disease that we’re still trying to understand. However, with this study and a similar study in the USA that has recently arrived at the same result using mice, the suspicion that the disease begins in the gut of some patients has gained considerable support,"

he adds.

The research at Aarhus University also showed that the harmful alpha-synuclein not only travel from the intestines to the brain, but also to the heart.

“For many years, we have known that Parkinson patients have extensive damage to the nervous system of the heart, and that the damage occurs early on. We’ve just never been able to understand why. The present study shows that the heart is damaged very fast, even though the pathology started in the intestine, and we can continue to build on this knowledge in our coming research,"

says Per Borghammer.

[1] Van Den Berge, N., Ferreira, N., Gram, H. et al. Evidence for bidirectional and trans-synaptic parasympathetic and sympathetic propagation of alpha-synuclein in rats. Acta Neuropathol (2019). https://doi.org/10.1007/s00401-019-02040-w

[2] Stokholm MG, Danielsen EH, Hamilton-Dutoit SJ, Borghammer P (2016) Pathological α-synuclein in gastrointestinal tissues from prodromal Parkinson disease patients. Ann Neurol 79:940–94

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