Defining the Role of Alpha-Synuclein in Enteric Dysfunction in Parkinson s Disease
Abstract
Parkinson s disease (PD) is typically recognized by a well-defined set of motor symptoms. However, over the last decade it has become increasingly clear that PD patients also suffer from a plethora of non-motor symptoms that are often more debilitating than the motor symptoms themselves. For instance, dysfunction of the enteric nervous system (ENS) causes gastrointestinal (GI) problems in 90% of PD patients including abnormal salivation, difficulties swallowing, constipation, and abnormal defecation. These symptoms have a tremendous negative impact on the quality of life of PD patients and also contribute to increased difficulties and costs associated with disease management. The underlying cause of GI dysfunction in PD is largely unknown. One reason for this gap in knowledge is the lack of appropriate model systems to study this pathology. Initial studies attempting to model GI dysfunction in PD relied on systemic administration of toxins. However, these studies produced a significant degree of overt cell death, which is absent in the human disorder. However, in recent years it has become evident that the protein alpha-synuclein (a-syn), which has been linked to the pathology in the brain that causes motor symptoms, may also cause GI symptoms. Indeed, abnormal forms of this protein, akin to those seen in the brain of the PD patient, are also found throughout the ENS, from the esophagus to the anus. To that end, in preliminary studies we investigated whether (abnormal) a-syn is also responsible for GI dysfunction. To do so, we developed a gene therapy method to overproduce a-syn in the descending colon of rats. Animals that overproduce a-syn in the colon are constipated, and further investigation indicated that this symptom was the result of reduced contraction of the muscle that controls the peristalsis of the GI tract. Our overarching goal is to test the hypothesis that accumulation of abnormal, pathological a-syn in the ENS causes GI dysfunction in PD. We will study gut function in rats for up to 1 year and perform a thorough characterization of the pathology that occurs following a-syn overproduction. Following the completion of the studies outlined in this proposal, we will: (1) have proven that pathological a-syn causes GI dysfunction in PD (in other words, we will have identified a therapeutic intervention point -- an area of emphasis for this funding opportunity), and (2) have characterized our new model of a-syn-mediated ENS dysfunction (i.e., addressed the development or progression of one or more non-motor manifestations of PD -- a second area of emphasis for this funding opportunity). This gene-therapy model of GI dysfunction can then be used as a platform to study the mechanisms and treatments for GI dysmotility in PD. These outcomes will positively impact the lives of PD patients by laying the foundation for new studies aimed at identifying therapeutic targets for the restoration of normal GI function. Ultimately, this will significantly increase the quality of life for PD patients, decrease morbidity, and improve the clinical management of PD motor symptoms. As mentioned above, following the completion of this proposal, we will have characterized a novel model of PD-related ENS dysfunction as it applies to pathology and progression of symptoms. This information will be shared with the scientific community (in the form of scientific manuscripts) and will provide rationale and background for other PD researchers upon which to design new research trials. Moreover, we will gladly share our gene therapy tools used to create this model with any interested investigator.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610676
Entities
People
- Fredric Manfredsson
Organizations
- Michigan State University
- United States Army