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New Model Confirms Gut-to-Brain Propagation of Parkinson’s Disease

Review of “Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson’s Disease” from Developmental Cell by Stuart P. Atkinson

The Braak hypothesis of Parkinson’s disease (PD) development states that α-synuclein can pass from the gut to the brain via the vagus nerve to initiate the formation of the aberrant aggregates that lead to the death of the dopamine neurons in the substantia nigra pars compacta [1, 2]. While the injection of preformed fibrils of α-synuclein into the striatum of mice results in dopaminergic neuron death consistent with retrograde transmission and long-range transport of pathogenic α-synuclein [2, 3], current protocols using preformed fibrils do not support the spread of pathologic α-synuclein from the gut to the brain.

However, researchers from the laboratories of Ted M. Dawson and Han Seok Ko (Johns Hopkins University School of Medicine, Baltimore, MD, USA) now describe a novel gut-to-brain α-synuclein transmission mouse model that employs the injection of pathological α-synuclein preformed fibrils into the duodenal and pyloric muscularis layer. Fascinatingly, Kim et al. report that this model faithfully mimics the spread of pathologic α-synuclein observed in PD [4, 5] and confirms the validity of Braak’s hypothesis [6].

Briefly, the authors assessed the spread of pathologic α-synuclein to and through brain following the injection of preformed fibrils into the duodenal and pyloric muscularis layer of the gut by detecting phosphorylation of serine 129 of α-synuclein. Their analysis first detected pathologic α-synuclein in the dorsal motor nucleus of the vagus, confirming gut-to-brain transport via the vagus nerve, and next in the caudal hindbrain followed later by detection in the substantia nigra pars compacta. Interestingly, the study observed the loss of dopaminergic neurons and the appearance of motor and non-motor symptoms associated with PD in a similar timeline as of the spread of pathologic α-synuclein from the gut to the brain. 

To confirm their results, the authors next assessed the spread of pathologic α-synuclein in the context of truncal vagotomy finding the hoped-for inhibition of gut-to-brain spread and any associated neurodegeneration and behavioral deficits associated with PD. Furthermore, the lack of PD-like symptoms in α-synuclein deficient model mice suggested that the appearance of PD-like pathologies and symptoms require endogenous α-synuclein.

Overall, the observations garnered from this new model support the Braak hypothesis and suggest that polysynaptic spreading of pathologic α-synuclein from the gastrointestinal tract via the vagus nerve to the substantia nigra pars compacta promotes the onset of symptoms that mimic those occurring in PD. The authors hope that their new findings will help to accelerate the study of the pathways associated with the trafficking of pathologic α-synuclein from the gut to brain in PD and associated diseases and will help to test therapeutic interventions to mitigate the risk of developing sporadic PD.

For more on how this new model of gut-to-brain propagation of PD may revolutionize the understanding and treatment of this disease, stay tuned to the Stem Cells Portal.

References

  1. Braak H, Tredici KD, Rüb U, et al., Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiology of Aging 2003;24:197-211.
  2. Braak H, Ghebremedhin E, Rüb U, et al., Stages in the development of Parkinson’s disease-related pathology. Cell and Tissue Research 2004;318:121-134.
  3. Mao X, Ou MT, Karuppagounder SS, et al., Pathological alpha-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science 2016;353.
  4. Gelpi E, Navarro-Otano J, Tolosa E, et al., Multiple organ involvement by alpha-synuclein pathology in Lewy body disorders. Movement Disorders 2014;29:1010-1018.
  5. Klingelhoefer L and Reichmann H, Pathogenesis of Parkinson disease—the gut–brain axis and environmental factors. Nature Reviews Neurology 2015;11:625.
  6. Kim S, Kwon S-H, Kam T-I, et al., Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson’s Disease. Neuron 2019.