Alpha-Synuclein Accumulation and Its Phosphorylation in the Enteric Nervous System of Patients Without Neurodegeneration: An Explorative Study

Alpha-synuclein (alpha-Syn) is widely distributed and involved in the regulation of the nervous system. The phosphorylation of alpha-Syn at serine 129 (p(Ser129)alpha-Syn) is known to be closely associated with alpha-Synucleinopathies, especially Parkinson's disease (PD). The present study aimed to explore the alpha-Syn accumulation and its phosphorylation in the enteric nervous system (ENS) in patients without neurodegeneration. Patients who underwent colorectal surgery for either malignant or benign tumors that were not suitable for endoscopic resection (n = 19) were recruited to obtain normal intestinal specimens, which were used to assess alpha-Syn immunoreactivity patterns using alpha-Syn and p(Ser129)alpha-Syn antibodies. Furthermore, the sub-location of alpha-Syn in neurons was identified by alpha-Syn/neurofilament double staining. Semi-quantitative counting was used to evaluate the expression of alpha-Syn and p(Ser129)alpha-Syn in the ENS. Positive staining of alpha-Syn was detected in all intestinal layers in patients with non-neurodegenerative diseases. There was no significant correlation between the distribution of alpha-Syn and age (p = 0.554) or tumor stage (p = 0.751). Positive staining for p(Ser129)alpha-Syn was only observed in the submucosa and myenteric plexus layers. The accumulation of p(Ser129)alpha-Syn increased with age. In addition, we found that the degenerative changes of the ENS were related to the degree of tumor malignancy (p = 0.022). The deposits of alpha-Syn were present in the ENS of patients with non-neurodegenerative disorders; particularly the age-dependent expression of p(Ser129)alpha-Syn in the submucosa and myenteric plexus. The current findings of alpha-Syn immunostaining in the ENS under near non-pathological conditions weaken the basis of using alpha-Syn pathology as a suitable hallmark to diagnose alpha-Synucleinopathies including PD. However, our data provided unique perspectives to study gastrointestinal dysfunction in non-neurodegenerative disorders. These findings provide new evidence to elucidate the neuropathological characteristics and alpha-Syn pathology pattern of the ENS in non-neurodegenerative conditions.