Michigan State University East Lansing United States
The most recognizable feature of Parkinsons disease PD is a set of well-defined motor symptoms that arise due to the loss of neurons in the substantia nigra SN. Nevertheless, it has become increasingly recognized that PD patients also suffer from a plethora of non-motor symptoms. Of those symptoms, gastrointestinal GI dysfunction is often described as extremely debilitating. Moreover, GI dysfunction can also complicate symptomatic management of the disease. Importantly, the same pathology that can be seen in the SN is also observed in the enteric nervous system ENS, the network of neurons that control GI function. In order to better study the role of this pathology aggregation of the protein alpha-synuclein -syn in enteric neurons, we devised a gene therapy method aimed at directly delivering a pathological dose of -syn to the ENS per se. This approach allows us to directly study the role of pathological -syn in the ENS, without the confound of inducing pathology in other neuronal populations. Our overarching hypothesis stated that that the pathological presence of aggregated -syn in the ENS impedes neuromuscular transmission responsible for propulsive colonic motility. We further proposes that colonic motilityand contractility will progressively decrease over time, without any overt neurodegeneration of the ENS as is the case with human disease. In year 1 we observed that 1 Low level of ectopic -syn overexpression in enteric neurons results in impaired contractility of the colon, and 2 This reduction in contractility is associated with a reduction of colonic motility.