Early and Persistent Expression of Phosphorylated α-Synuclein in the Enteric Nervous System of A53T Mutant Human α-Synuclein Transgenic Mice

Abstract

Alpha-synuclein is a key protein in Parkinson disease (PD) and dementia with Lewy bodies. It is found in Lewy bodies in the brains of PD patients and has been reported in the peripheral nervous system in postmortem tissues from PD patients and in biopsies from patients in the preclinical phase of PD. Here, we used a transgenic mouse model of human synucleinopathies expressing the A53T mutant α-synuclein (TgM83) in which a neurodegenerative process associated with α-synuclein occurs spontaneously and increases with age. In particular, α-synuclein protein phosphorylated at serine 129 (pSer129 α-synuclein) naturally and progressively increases in diseased brains. We examined the time course of pSer129 α-synuclein presence in the gut of these mice between 1.5 and 22 months of age using immunohistochemistry and paraffin-embedded tissue blots. The pSer129 α-synuclein accumulated early (before the onset of motor signs) and persistently in the enteric nervous system and was concomitantly found in the brain. These results suggest that the accumulation of phosphorylated α-synuclein in the enteric and central nervous systems may result from parallel pathologic processes when the disease is linked to a mutation of α-synuclein.

Neurotoxin-Induced Catecholaminergic Loss in the Colonic Myenteric Plexus of Rhesus Monkeys

“…For example, transgenic mice overexpressing human wild type α-synuclein had increased α-synuclein immunoreactivity surrounding cholinergic neurons in the colonic myenteric plexus and decreased fecal output at 8–10 months of age [43] and, in a separate study, displayed increased insoluble colonic myenteric α-synuclein and constipation (reduced fecal pellet output and fecal water content) at 12–15 months [44]. In addition, transgenic mice expressing human A53T α-synuclein, a mutation associated with familial, early-onset PD, had accumulation of insoluble phosphorylated α-synuclein in the ENS [45], decreased stool frequency and fecal water content [46,47] and increased α-synuclein protein and transcript levels in the colon [47]. Although changes in enteric α-synuclein were not reported for the nonhuman primate systemic MPTP model [34], analysis at varying timepoints in neurotoxin-induced rodent models of PD has produced diverse results.…”

Microbiome–microglia connections via the gut–brain axis

“…According to Braak's hypothesis, aggregation of α-synuclein spreads from the enteric nervous system to the brain via the vagus nerve in cases of sporadic PD (Braak et al, 2004;Rietdijk et al, 2017). Evidence for this theory is supported by both preclinical and clinical evidence demonstrating the presence of α-synuclein deposits in enteric neurons of the gut before the detection of misfolded α-synuclein in the CNS (Braak et al, 2004;Bencsik et al, 2014). While this pattern of α-synuclein spreading is not observed in all cases of sporadic PD, vagotomy may be associated with reduced risk of developing PD in humans, potentially implicating peripheral influences on disease development (Svensson et al, 2015;Liu et al, 2017).…”

Oral administration of Proteus mirabilis damages dopaminergic neurons and motor functions in mice

“…Both accumulated α-synuclein and 3-nitrotyrosine, which induce apoptotic cell death in dopaminergic neurons 11 , are increased significantly in colonic submucosal nerve fibers of early PD subjects versus healthy controls 12 , 13 . Accumulated α-synuclein was observed in the intestine and brain of Thy1-α-syn or A53T mutant α-syn transgenic mice before the onset of motor signs 14 , 15 . Moreover, it was shown experimentally that monomeric, oligomeric, and fibrillar α-synuclein forms can migrate from the gut to the brain via the vagal nerve 16 .…”