Nonmotor symptoms, particularly hyposmia and constipation, precede the motor symptoms of Parkinson disease (PD) by many years, and the lifetime risk of PD negatively correlates with the frequency of bowel movements
Neurodegeneration in PD seems to start in the olfactory bulb, the enteric nervous system, the dorsal motor nucleus of the vagus nerve and the intermediolateral nucleus in the thoracic and sacral spinal cord
Evidence suggests that environmental factors have an important role in triggering and/or propagating the pathology of PD; the olfactory and gastrointestinal systems are gateways to the environment
Chronic intragastral administration of rotenone in mice has resulted in neuropathology and symptoms typical of PD that developed in a chronological and regional sequence that corresponds to the Braak staging system
PD pathology that involves α-synuclein spreads from the enteric nervous system to the CNS by trans-synaptic cell-to-cell transmission in intact sympathetic and parasympathetic nerves
α-Synuclein impairs mitochondrial activity and causes oxidative stress in neurons, especially dopaminergic neurons in the substantia nigra and noradrenergic neurons in the locus coeruleus
Parkinson disease (PD) follows a defined clinical pattern, and a range of nonmotor symptoms precede the motor phase. The predominant early nonmotor manifestations are olfactory impairment and constipation. The pathology that accompanies these symptoms is consistent with the Braak staging system: α-synuclein in the dorsal motor nucleus of the vagus nerve, the olfactory bulb, the enteric nervous system (ENS) and the submandibular gland, each of which is a gateway to the environment. The neuropathological process that leads to PD seems to start in the ENS or the olfactory bulb and spreads via rostrocranial transmission to the substantia nigra and further into the CNS, raising the intriguing possibility that environmental substances can trigger pathogenesis. Evidence from epidemiological studies and animal models supports this hypothesis. For example, in mice, intragastric administration of the pesticide rotenone can almost completely reproduce the typical pathological and clinical features of PD. In this Review, we present clinical and pathological evidence to support the hypothesis that PD starts in the gut and spreads via trans-synaptic cell-to-cell transfer of pathology through the sympathetic and parasympathetic nervous systems to the substantia nigra and the CNS. We also consider how environmental factors might trigger pathogenesis, and the potential for therapeutically targeting the mechanisms of these initial stages.
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The authors are very thankful for the provision of Figure 1c by M. Meinhardt and G. Baretton at Neuropathology, Institute of Pathologie, Technical University Dresden, Germany and of Figure 2b and 2c by W. J. Schulz-Schaeffer at the Prion and Dementia Research Unit, Neuropathology, University Medical Center Göttingen, Germany.
H.R. has served on the advisory boards of, given lectures for and received research grants from Abbott, Abbvie, Bayer Health Care, Boehringer Ingelheim, Brittania Pharmaceuticals, Cephalon, Desitin, GlaxoSmithKline, Lundbeck, Medtronic, MerckSerono, Novartis, Orion Pharma, Pfizer, Teva Pharmaceutical Industries, UCB, Valeant Pharmaceutical International, and Zambon. L.K declares no competing interests.
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Klingelhoefer, L., Reichmann, H. Pathogenesis of Parkinson disease—the gut–brain axis and environmental factors. Nat Rev Neurol 11, 625–636 (2015). https://doi.org/10.1038/nrneurol.2015.197
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