Defining the Role of Alpha-Synuclein in Enteric Dysfunction in Parkinson's Disease
Abstract
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 (alpha-syn) in enteric neurons, we devised a gene therapy method aimed at directly delivering a pathological dose of alpha-syn to the ENS per se. This approach allows us to directly study the role of (pathological) alpha-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 alpha-syn in the ENS impedes neuromuscular transmission responsible for propulsive colonic motility. We further proposes that colonic motility and 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 alpha-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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2020
- Accession Number
- AD1103054
Entities
People
- Fredric P. Manfredsson
Organizations
- Michigan State University