Gastrointestinal dysfunction has long been noted as an early feature of Parkinson’s disease, and “in many cases demands stimulating medicines of very considerable power” (James Parkinson, 1817). Epidemiological studies have validated the observation, noting that constipation and gastrointestinal disorders precede the onset of motor symptoms by at least two or three decades. Post-mortem studies on PD patients show that Lewy bodies containing pathologic aggregated alpha-synuclein is found in both the gut and brain, and Braak and colleagues recently suggested a link between the two. In an intriguing study with post-mortem human autopsy materials, Braak and colleagues showed that pathologic synuclein aggregates appear in the enteric nervous system prior to brainstem involvement and may define early disease pathophysiology (H. Braak, 2006). We plan to directly test the hypothesis that chronic inflammation in the gut may be a trigger for Parkinson’s disease in genetically susceptible individuals.
We propose to test the hypothesis that enteric inflammation may act as a "second hit" to exacerbate synuclein pathology in the autonomic and central nervous systems. We will undertake this by creating chronic gastrointestinal inflammatory condition in rodent models of Parkinson's disease using Dextran Sodium Sulfate to chemically induce chronic colitis. For our studies, we will employ transgenic models overexpressing a P1 artificial chromosome (PAC) containing the entire wild-type human alpha-synuclein gene, including the promoter and regulatory regions. This model mirrors human alpha-synuclein duplication with three genomic copies of the gene on a diploid murine alpha-synuclein background. Though this rodent model does not display overt neuropathology, we expect that DSS-induced colitis will lead to chronic cell-mediated as well as humoral immunity mediated inflammatory phenotype in the gut which may lead to exacerbation of pathologic synuclein aggregation in this transgenic rodent model.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Our hypothesis will test whether environmental factors can exacerbate PD-related neuropathology on a background of genetic vulnerability. If our working hypothesis is tested true, then anti-inflammatory therapies can be incorporated in future clinical trials.
This study will provide a mechanistic understanding of the role of epigenetic factors in the etiology of sporadic PD progression.
Inflammation, as a “second-hit” candidate, may exacerbate the neurodegenerative process by inducing mitochondrial dysfunction, oxidative stress and apoptosis of dopaminergic neurons during the early symptom period in PD. To investigate this hypothesis and to test whether chronic gut inflammation may lead to increased nigro-striatal dysfunction, we examined the effects of chronic colitis in the brains of wild type and human synuclein transgenic mice. Colitis was induced chemically by administration of three consecutive cycles of Dextran Sodium Sulphate (DSS) in drinking water for 6 days followed by normal drinking water for 21 days.
Following DSS treatment, chronic gut inflammation and cell loss were evident. Chronic inflammation resulted in increased activation of glial cells in the brain in both types of mice brains treated with DSS. No changes in DARPP32 immunopositive neurons (dopamine neurons) or processes were evident in either type of mice. However, intracellular synuclein immunoreactivity was increased in the striatal neurons of DSS treated wild type mice, suggesting endogenous mouse synuclein dysfunction. No such changes were readily apparent in the human synuclein transgenic mice brain or spinal cord. Significant downregulation in D2 receptor and Tyrosine hydroxylase transcript levels in the midbrains of DSS treated WT mice were also noted. Further investigation is being performed to completely characterize the role of peripheral inflammation on synuclein dysfunction.