Researchers from Johns Hopkins Medicine (MD, USA) have provided additional evidence to support the idea that Parkinson’s disease originates among cells in the gut and travels up the vagus nerve to the brain. This pathway was observed in a new mouse model, which recapitulates both motor and non-motor deficits as well as early-stage and late-stage features associated with Parkinson’s disease.
The results of their study have been published in the journal Neuron.
“Since this model starts in the gut, one can use it [to] study the full spectrum and time course of the pathogenesis of Parkinson’s disease,” commented said Ted Dawson (Johns Hopkins University), co-senior author of the study. “For instance, one could test preventive therapies at early pre-symptomatic stages of Parkinson’s disease all the way to full-blown Parkinson’s disease in one animal model.”
In 2003, Heiko Braak – a German neuroanatomist – and colleagues proposed that α-synuclein pathology can spread from the GI tract via the vagus nerve to the substantia nigra pars compacta (SNc), where it is then believed to selectively kill dopamine-producing neurons.
In this new study, researchers developed a mouse model that supports Braak’s hypothesis. The team injected mouse α-synuclein preformed fibrils into the gastrointestinal muscles densely innervated by the vagus nerve.
At 1 month after injection, the investigators observed that pathologic α-synuclein had spread to the dorsal motor nucleus of the vagus, located in the lowest part of the brainstem; this corresponds to Braak’s stage one. Within 3 months, pathologic α-synuclein had spread up the brainstem to the locus coeruleus and higher to the SNc, and even reached beyond the brainstem to the amygdala, hypothalamus and prefrontal cortex, corresponding to later Braak stages. By 7 months, pathologic α-synuclein had spread to additional brain regions, including the hippocampus, striatum and olfactory bulb.
The researchers also noted that by this time, there was significant loss of dopamine-producing neurons in the SNc and striatum. In addition to motor deficits, mice that received gastrointestinal injections of α-synuclein preformed fibrils also developed signs of depression and anxiety, olfactory dysfunction and cognitive deficits affecting spatial learning and memory, novel object recognition, fear memory and working memory.
Transmission of pathologic α-synuclein from the gut to the brain, and the resulting neuronal death and symptoms, did not occur in mice whose vagal nerve fibers were cut.
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Although the researchers believe that these findings strongly support Braak’s hypothesis, they noted that it may be difficult to provide the same kind of evidence for the gut–brain connection in humans. However, studies in humans have revealed that truncal vagotomy – a specific surgical procedure on the vagus nerve – may reduce the risk of Parkinson’s disease.
In the future, the investigators plan to assess whether these findings extend to non-human primates. They also intend to investigate the underlying mechanisms that result in the spread of pathologic α-synuclein from the gut to the brain and the resulting motor and non-motor symptoms. Potential biomarkers will also be examined that are associated with early pre-symptomatic stages of the disease, and potential therapeutic interventions that interfere with the spread of pathologic α-synuclein will be investigated.
Sources: Kim S, Kwon S-H, Lee H et al. Transneuronal propagation of pathologic α-synuclein from the gut to the brain models Parkinson’s disease. Neuron doi:10.1016/j.neuron.2019.05.035 (2019) (Epub ahead of print); www.eurekalert.org/pub_releases/2019-06/cp-nmm061919.php