Ultrastructural perspectives on the enteric nervous system in Parkinson's disease

The enteric nervous system (ENS), a central component of the gut-brain axis, is increasingly recognized as an important site in the pathogenesis of neurodegenerative diseases. In Parkinson's disease (PD) in particular, gastrointestinal dysfunction and pathological changes within the ENS often precede symptoms in the central nervous system (CNS). According to the Braak hypothesis, disease-associated pathology may originate in the gastrointestinal tract and spread to the brain via neural pathways such as the 10 ^th cranial nerve, the vagus nerve. Consequently, the ENS is considered a potential early site of neurodegenerative processes. Despite this growing interest, most studies investigating ENS pathology rely on fluorescence-based approaches that primarily provide information on protein expression and cellular distribution. While these techniques have advanced our understanding of enteric neuronal networks, they offer limited insight into subcellular organization. Ultrastructural analysis of the CNS has already identified characteristic changes at the subcellular level, including morphological alterations of synapses, changes in the endolysosomal system, and mitochondrial dysfunction. Mitochondrial dysfunction represents a key mechanism in PD, as demonstrated in toxin models such as rotenone exposure and in genetic forms involving mutations in PINK1 or PRKN. However, comparable ultrastructural investigations of the ENS remain scarce. This review highlights the importance of ultrastructural investigations of the ENS for understanding early neurodegenerative processes and discusses how electron microscopy (EM) may reveal previously underappreciated cellular and subcellular alterations in enteric neurons. Particular attention is given to mitochondrial pathology and the need for systematic ultrastructural analyses of the ENS in models and human studies of PD.