Gastrointestinal Function in Parkinson's Mice

Promising Outcomes of Original Grant:
Our original project was designed to screen several well-known models of Parkinson’s disease to determine if any mimic the gastrointestinal symptoms (constipation, nausea, bloating) that are so common and disabling for PD patients. We described abnormal GI function and abnormal neuropathophysiology in the enteric nervous system (ENS), the semi-autonomous network of nerves that controls digestion, in all of the models we examined. Several of these findings appear to be related to either abnormal accumulation of the PD-related protein alpha-synuclein or abnormal function of the neuronal signal dopamine in the ENS.
Objectives for Supplemental Investigation:
Our completed work has raised two particularly pressing questions, the answers to which will substantially drive research into GI symptoms in PD in the future. First, alpha-synuclein accumulates in the enteric nervous system of transgenic mice in a way that is similar in quality to that seen in PD. We will determine the effects of advancing age on GI symptoms in these mice in an attempt to define a model in which to study the combined effects of genetic and environmental insults on PD GI symptoms and their cause. Second, several of the model systems had behavioral and/or pathological abnormalities in the GI system related to abnormal dopamine function, a finding that has been described previously in PD patients. Confirming that in mice by attempting to normalize GI motility using drugs that affect dopamine receptors is an important step toward characterizing the effects of dopamine depletion on GI function and the impact of dopamine drugs on GI symptoms in PD.
Importance of This Research for the Development of a New PD Therapy
Proving our hypotheses would provide two main outcomes to assist in the development of treatments for GI symptoms in PD. First, alpha-synuclein mice may provide an accurate and effective model in which to screen potential therapies for GI symptoms specifically related to PD. Second, since PD patients have a decrease in dopamine in the GI tract similar to that found in the brain, investigation into the effects of dopamine on the digestive system will help to define specific treatments for GI symptoms in PD.