Research Fellow, Florey Institute of Neuroscience and Mental Health
Parkinson's disease (PD) is the second most common neurological disease in Australia, affecting more than 80,000 people annually. Characterized by progressive degeneration of nigrostriatal dopaminergic neurons, PD is associated with motor impairments such as rigidity, resting tremor, postural instability, and bradykinesia as well as autonomic dysfunction, often presenting as gastrointestinal (GI) dysfunction. Between 80-90% of people with PD suffer from GI dysfunction, most commonly constipation which often precedes the onset of motor deficits by decades. GI dysfunction has been correlated with abnormalities in the enteric nervous system (ENS). Studies focusing on the ENS of patients with Lewy body diseases have found αsynuclein in the ENS of nearly every patient with PD. Neuronal loss and neurochemical changes have been observed in the ENS of patients with PD and a positive correlation between gut permeability and intestinal levels of αsynuclein has been observed in untreated patients with early PD. Enteric neurons, therefore, may be involved in gastrointestinal dysfunction and PD initiation and development. However, the relationship between ENS and central nervous system (CNS) deterioration, motor deficits and GI dysfunctions remains unclear. New evidence strongly suggests that the pathogenesis of PD involves trans-synaptic cell-to-cell transmission of PD pathology from the ENS via the vagus nerve to the CNS. The work outlined here aims to use mouse models of PD to systematically investigate structural and functional deterioration in the ENS and CNS to uncover the temporal and causal relations between development of motor symptoms and GI dysfunction. This work will provide key locations in the CNS and ENS at which to target therapy and determine whether enteric neuroprotection is a viable therapeutic for PD.
Abstract: Parkinson's disease is a progressive neurodegenerative disease that affects millions of elderly individuals worldwide. Despite intensive efforts dedicated to find a better treatment, the pathogenesis of Parkinson's Disease remains unknown. In search for a better therapy for the disease, several new in vivo and in vitro models of Parkinson´s disease have been developed in recent times. Areas covered: The authors provide an outline of the various traditional models of Parkinson´s disease and address those that have been recently generated. They also discuss the utility of these models for the identification of drugs of potential therapeutic value for Parkinson´s Disease patients. From the cell based models and the well-known toxin-based animal models, to the recent genetic models and the increasingly used non-mammalian models, every model is worthwhile in the search for a better Parkinson´s Disease therapy. Expert opinion: Almost 60 years after its discovery, levodopa is still the gold standard treatment for Parkinson's Disease patients. It seems unlikely that a single model can fully recapitulate the complexity of Parkinson's Disease in the same way it appears improbable that a unique treatment could relieve both the motor and non-motor symptoms of Parkinson's Disease altogether. Therefore treatment will probably require a combination of therapies.
Pub.: 25 Jan '18, Pinned: 21 Mar '18
Abstract: Our understanding of dysfunction of the gastrointestinal system in patients with Parkinson's disease has increased substantially in the past decade. The entire gastrointestinal tract is affected in these patients, causing complications that range from oral issues, including drooling and swallowing problems, to delays in gastric emptying and constipation. Additionally, small intestinal bacterial overgrowth and Helicobacter pylori infection affect motor fluctuations by interfering with the absorption of antiparkinsonian drugs. The multifaceted role of the gastrointestinal system in Parkinson's disease necessitates a specific and detailed assessment and treatment plan. The presence of pervasive α-synuclein deposition in the gastrointestinal tract strongly implicates this system in the pathogenesis of Parkinson's disease. Future studies elucidating the role of the gastrointestinal tract in the pathological progression of Parkinson's disease might hold potential for early disease detection and development of neuroprotective approaches.
Pub.: 20 May '15, Pinned: 21 Mar '18
Abstract: Parkinson's disease (PD) is a neurodegenerative disorder which leads to severe movement impairment; however, Parkinsonian patients frequently suffer from gastrointestinal (GI) problems which at present are poorly understood, scarcely investigated, and lack an effective cure. Traditionally, PD is attributed to the loss of mesencephalic dopamine-containing neurons; nonetheless, additional nuclei, such as the dorsal motor nucleus of the vagus nerve and specific central noradrenergic nuclei, are now identified as targets of PD. While the effects of PD on the somatic motor systems are well characterized, the influence on the digestive system still needs to be clarified. Recent findings demonstrate the occurrence of pathological alterations within peripheral neuronal networks in the GI tract of Parkinsonian patients. However, it remains unclear whether a real cell loss occurs, and whether this happens specifically for a subclass of autonomic neurons or if it reflects the sole loss of autonomic nerves. This review summarizes the neurochemical and morphological changes which might be responsible for impaired GI motility. Moreover, we focus on the experimental models to reproduce the altered digestive system of Parkinsonian patients since an experimental model able to mimic such features of PD is required. In the last part of the manuscript, we suggest potential therapeutic targets.
Pub.: 19 Jun '08, Pinned: 21 Mar '18
Abstract: Patients with Parkinson's disease often experience non-motor symptoms including constipation, which manifest prior to the onset of debilitating motor signs. Understanding the causes of these non-motor deficits and developing disease modifying therapeutic strategies has the potential to prevent disease progression. Specific neuronal subpopulations were reduced within the myenteric plexus of mice 21 days after intoxication by the intraperitoneal administration of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and was associated with a reduction in stool frequency, indicative of intestinal dysfunction. Oral administration of the divalent copper complex, Cu(II)(atsm), which has been shown to be neuroprotective and restore motor performance to MPTP lesioned mice, improved stool frequency and was correlated with restoration of neuronal subpopulations in the myenteric plexus of MPTP lesioned mice. Restoration of intestinal function was associated with reduced enteric glial cell reactivity and reduction of markers of inflammation. Therapeutics that have been shown to be neuroprotective in the central nervous system, such as Cu(II)(atsm), therefore also provide symptom relief and are disease modifying in the intestinal tract, suggesting that there is a common cause of Parkinson's disease pathogenesis in the enteric nervous system and central nervous system.
Pub.: 30 Jul '16, Pinned: 21 Mar '18