Objective: The aim of this study was to determine if mice overexpressing the human mutation of alpha-synuclein develop gastrointestinal (GI) dysfunction, and to understand the time course of events in relation to central nervous system (CNS) dysfunction.

Background: GI dysfunction, such as prolonged GI transit time and constipation, has been associated with the pathological changes seen in the brain, and often precedes the onset of motor symptoms in Parkinson’s disease (PD) by decades. A hallmark of PD is the aggregation of the protein alpha-synuclein in various regions of the brain, which has been strongly linked to nerve cell death. Aggregates of alpha-synuclein are also found in the enteric nervous system of PD patients and may be a cause of enteric neuron damage and subsequent GI dysfunction.

Methods: We performed a complete characterization of the GI phenotype in the A53T mouse model of PD, which overexpresses the human mutation of alpha-synuclein driven by the mouse prion promoter. GI and motor function were monitored at one month intervals from 18-80 weeks. Constipation, colon motility, and GI transit were assessed using the fecal pellet output test, bead expulsion test, and whole-gut transit test, respectively. Motor deficits were monitored using the beam traversal test.

Results: When compared with WT mice, A53T mice developed progressive GI dysfunction from 58 weeks of age, which included reduced colon motility and whole gut transit (P<0.05). Interestingly, motor deficits were observed prior to the onset of GI symptoms in A53T mice from 32 weeks of age, indicating that in this mouse model CNS dysfunction precedes the manifestation of GI symptoms.

Conclusions: Mice overexpressing the human mutation of alpha-synuclein, driven by the mouse prion promoter, develop GI dysfunction after the onset of motor deficits. Although this model may not fully reproduce the human condition, it continues to serve as a useful tool to understand both the CNS and GI dysfunction associated with PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/characterization-of-the-gastrointestinal-dysfunction-in-mice-overexpressing-the-human-mutation-a53t-of-alpha-synuclein/