Restoration of intestinal function in an MPTP model of Parkinson's Disease.

Parkinson’s Disease (PD) is a neurodegenerative disorder characterized by chronic and progressive motor impairment including dyskinesia, rigidity, instability, and tremors1. Patients also experience significant non-motor symptoms including hyposmia, REM-sleep behaviour disorders, depression, and constipation2. These non-motor symptoms have recently been recognized as pre-motor features of PD and may be early markers of disease. While the etiology of idiopathic PD is unclear it is characterized by the presence of Lewy bodies and Lewy neurites, which are primarily composed of α-synuclein, and the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc)2. These pathologies correlate with the subsequent motor disturbances experienced by patients. In addition to classic motor disturbances virtually all PD patients develop some level of autonomic dysfunction, including those affecting the gastrointestinal tract3. It is not clear whether gastrointestinal symptoms are the consequence of a loss of extrinsic innervations arising from neuronal loss in the central nervous system (CNS) or a primary consequence of pathogenesis in the enteric nervous system (ENS). However, epidemiological and histological studies suggest that gastrointestinal symptoms (constipation) and α-synuclein inclusions are present in the ENS many years before the onset of motor symptoms and inclusions occur in the CNS4,5. Furthermore recent studies highlighting the ability of α-synuclein to undergo ‘prion-like’ misfolding and aggregation6,7 are consistent with the hypothesis that disease may originate in the peripheral organs such as the ENS and progress to the CNS via the dorsal motor nucleus of the vagus where this pathological process would systematically affect the brain stem, mid- and fore-brain and eventually the cerebral cortex4,8. The ENS is the division of the autonomic nervous system that provides intrinsic control of the gastrointestinal system9. The neurons of the ENS are organised into two major sets of ganglia; the myenteric plexus (MP) located between the longitudinal and smooth muscle layers, and the submucosal plexus (SMP) found in the submucosa. The function of the gastrointestinal tract is also influenced by extrinsic innervations that arise from the dorsal motor nucleus of the vagus to promote increased gut motility and sympathetic innervations from the spinal ganglia to inhibit gastric motility. The neuronal types in the ENS include primary afferent neurons, interneurons and motor neurons (inhibitory or excitatory). Most neurons involved with gastrointestinal motility are found in the myenteric plexus. Animal models have been instrumental in our understanding of the pathogenesis of PD. Chemical induction of lesions using MPTP, rotenone or 6-OHDA; the expression of α-synuclein encoding mutations associated with familial PD; or the seeding of brain with α-synuclein have all been shown to induce motor changes and pathology consistent with PD10. Relatively few studies have examined the ENS, those that have show changes in neuronal populations, accumulation of α-synuclein and changes in gastrointestinal function11. α-synuclein has been reported to aggregate in the myenteric neurons of hA53T transgenic mice and propagate from the gut to the brain in rats following injection of human brain extracts containing aggregated α-synuclein suggesting the potential for transmission of synucleinopathy in the ENS8,12. Current therapeutic strategies achieve symptomatic relief of the motor symptoms of PD by providing dopamine precursors, dopamine agonists, or inhibiting dopamine breakdown but do not address the underlying pathogenesis of the disorder2. Dopamine precursors have also been reported to improve non-motor symptoms13, although treatments for non-motor functions remain largely inadequate and are directed to symptom relief. Disease modifying therapies that target the underlying pathogenesis of disease offer the possibility of slowing or stopping the underlying neurodegeneration process. Mitochondrial dysfunction, oxidative stress, inflammation and protein mishandling are likely and interrelated mechanisms of CNS pathology in patients with PD. A reactive gliosis involving astrocytes and microglial cells is observed in regions of neurodegeneration in patients with PD14. This may be a protective mechanism, elicited in response to cell death to clear extracellular debris and produce neurotrophic factors to support neuron survival. But it may equally contribute to pathogenesis through the production of reactive oxygen (ROS) and nitrogen species. CuII(atsm) is a copper loaded thiosemicarbazone that has been used for the diagnosis and treatment of cancer and has been shown to delay disease in several models of neurodegeneration15,16,17. The therapeutic efficacy of CuII(atsm) has been attributed to its metal chelator activity and antioxidant/ROS scavenging capacity, both of which are likely to impact on the mechanisms of PD and has, as a consequence, the potential to offer both disease modifying and symptom relieving therapy. In support of this treatment of mouse models of PD with CuII(atsm) improved motor and cognitive function and rescued nigral cell loss15. In the current study the effect of CuII(atsm) on intestinal function and pathology in MPTP lesioned mice is described.