Assessment of gastrointestinal function and enteric nervous system changes over time in the A53T mouse model of Parkinson's disease.

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Gastrointestinal (GI) dysfunctions, including constipation and delayed stomach emptying, are prevalent and debilitating non-motor symptoms of Parkinson's disease (PD). These symptoms have been associated with damage in the enteric nervous system (ENS) and the accumulation of pathogenic alpha-synuclein (α-Syn) within the GI tract. While motor deficits and dopaminergic neuron loss in the central nervous system (CNS) of the A53T mouse model are well-characterised, the temporal relationship between GI dysfunction, ENS pathology, and motor symptoms remains unclear. This study aimed to investigate functional alterations in the GI tract at the early stages of the disease, before the appearance of motor deficits, both in vivo and ex vivo. Early colonic motility deficits observed in A53T mice, measured via bead expulsion, preceded motor impairments emerged at 36 weeks. Although whole-gut transit remained unchanged, reduced faecal output was concurrent with marked colonic dysmotility at 36 weeks. Despite a lack of significant neuronal loss, a greater number of enteric neurons in A53T mice showed signs of neuronal hypertrophy and increased nuclear translocation of HuC/D proteins indicative of neuronal stress at 12 and 36 weeks. Calcium imaging revealed differential enteric neuron activity, characterised by exaggerated calcium transients at 12 weeks that normalized by 36 weeks. Furthermore, a reduction in enteric glial populations was observed as early as 12 weeks in both the ileum and colon of A53T mice. These findings provide compelling evidence that ENS pathology, including neuronal stress, disrupted calcium signalling, and glial cell loss, precedes the onset of motor symptoms and may contribute to early GI dysfunction in PD.

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