Parkinson's disease (PD) is typically recognized as a somatic motor disorder. However, gastrointestinal motor dysfunction resulting in constipation is often described as having a greater negative impact on the quality of life than somatic motor dysfunction. Moreover, GI dysfunction complicates the clinical management of PD as it interferes with the absorption of levodopa, the standard treatment for PD motor symptoms. The protein alpha- synuclein (?-syn) is linked to CNS degeneration and is present in aggregated forms in neurons throughout the enteric nervous system (ENS). Overexpression of ?-syn in specific populations of DA neurons in the CNS results in ?-syn aggregation, altered neurotransmission, and neurodegeneration; providing a model with high face validity for PD. However, to date, no attempts have been made linking pathological enteric ?-syn to GI dysfunction. To that end, we developed a novel gene delivery method whereby we can direct transgene expression specifically to enteric neurons. Importantly, this approach limits all transgene expression to the ENS with no expression seen in central neurons, muscle, or other organs. In other words, we have developed a novel platform by which to study ENS function without adding confound of using systemically applied agents such as toxicants or the use of transgenic animals with ubiquitous transgene expression. Using this approach we delivered adeno-associated virus (AAV) expressing ?-syn to the descending colon. Within one month of vector delivery the animals displayed a significant decrease in fecal output, decreased inhibitory neuromuscular transmission, and decreased basal levels of calcium in neurons and enteric glia, without neuronal loss in the treated ENS. ?-syn has a role in synaptic vesicle exocytosis, recycling, and docking, and aggregation of ?-syn results in impaired neurotransmission. We therefore hypothesize that ?-syn contributes to GI dysfunction, and that this effect is mediated via impaired synaptic transmission, resulting in a net increase of the inhibitory tone of the ENS. Herein we propose to (1) Determine whether ?-syn aggregation is required for the observed colonic dysmotility. (2) Determine whether overexpression of ?-syn results in a net increase in the inhibitory tone of ENS neurotransmission and whether this impairs propulsive motility. (3). Determine whether ?-syn overexpression impairs enteric ganglionic neurotransmission. We will perform these analyses by using vectors that encode different isoforms of ?-syn (wildtype, hyper-aggregatable, and non-aggregatable). We will compare the data observed in treated rats and mice with transgenic ?-syn overexpressing animals. We will also determine whether ?-syn overexpression in inhibitory motor neurons (the population of ENS neurons most often associated with ?-syn pathology in PD) per se is sufficient to elicit GI dysfunction. Together the aims in this proposal intend to demonstrate that aggregated ?-syn in the ENS causes GI dysfunction, and to define the molecular etiology underlying GI dysfunction in PD. This work will thus provide a basis for future research efforts focused on investigating new treatments of this devastating comorbidity in PD.

Public Health Relevance

The aim of this project is to investigate the causative role the protein alpha-synuclein (?-syn) in gastric dysmotility associated with Parkinson's disease (PD). Although ?-syn has been intimately tied to PD- associated neurodegeneration of the central nervous system and identified in the enteric nervous system of PD patients, the potential role of this protein in GI dysfunction has never been investigated. We propose to utilize a combination of gene therapy and electrophysiology to define the (pathological) role of ?-syn in enteric nervous system dysfunction, and thereby potentiate the discovery of novel therapeutic targets for the treatment of this debilitating comorbidity.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
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Shea-Donohue, Terez
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Dignity Health
San Francisco
United States
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