Gastric Enteric Glial Cells: A New Contributor to the Synucleinopathies in the MPTP-Induced Parkinsonism Mouse

Abstract

Accumulating evidence has shown that Parkinson’s disease (PD) is a systemic disease other than a mere central nervous system (CNS) disorder. One of the most important peripheral symptoms is gastrointestinal dysfunction. The enteric nervous system (ENS) is regarded as an essential gateway to the environment. The discovery of the prion-like behavior of α-synuclein makes it possible for the neurodegenerative process to start in the ENS and spread via the gut-brain axis to the CNS. We first confirmed that synucleinopathies existed in the stomachs of chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/probenecid (MPTP/p)-induced PD mice, as indicated by the significant increase in abnormal aggregated and nitrated α-synuclein in the TH-positive neurons and enteric glial cells (EGCs) of the gastric myenteric plexus. Next, we attempted to clarify the mechanisms in single MPTP-injected mice. The stomach naturally possesses high monoamine oxidase-B (MAO-B) activity and low superoxide dismutase (SOD) activity, making the stomach susceptible to MPTP-induced oxidative stress, as indicated by the significant increase in reactive oxygen species (ROS) in the stomach and elevated 4-hydroxynonenal (4-HNE) in the EGCs after MPTP exposure for 3 h. Additionally, stomach synucleinopathies appear before those of the nigrostriatal system, as determined by Western blotting 12 h after MPTP injection. Notably, nitrated α-synuclein was considerably increased in the EGCs after 3 h and 12 h of MPTP exposure. Taken together, our work demonstrated that the EGCs could be new contributors to synucleinopathies in the stomach. The early-initiated synucleinopathies might further influence neighboring neurons in the myenteric plexus and the CNS. Our results offer a new experimental clue for interpreting the etiology of PD.

A probiotic formulation protects the dopaminergic neurons via attenuating the intestinal inflammation in mice of Parkinson’s disease

“…Gastrointestinal tract has been proven to be more vulnerable to MPTP injection than the dopaminergic neurons in the brain [21] and twice subacute MPTP administrations induce in ammation in the gut, in particular ileum [22]. To investigate the intestinal in ammatory responses to MPTP injection, the mRNA expression level of cytokines was measured in the intestine tissue.…”

“…Conventionally, MPTP is thought to be a neurotoxin targeting dopaminergic neurons in the substantia nigra [33]. However, gastrointestinal tract has been proven to be more vulnerable to MPTP injection than the dopaminergic neurons in the brain [21]. The intestine has considerably high levels of MPTP or its metabolites in the C57BL/6 mouse 8 h after MPTP injection [34].…”

“…Gastrointestinal tract has been proven to be more vulnerable to MPTP than the dopaminergic neurons in the brain [21] and twice subacute MPTP administrations induce in ammation in the gut, in particular ileum [22]. The PD mice receiving subacute administration of MPTP was employed in the present study to investigate the neuroprotective effects of VSL#3 ® , speci cally the dopaminergic neurons, as well as the intestinal anti-in ammation-related mechanism.…”

From the Gut to the Brain: The Role of Enteric Glial Cells and Their Involvement in the Pathogenesis of Parkinson’s Disease

“…The uricosuric agent probenecid coadministered with the dopaminergic neurotoxin MPTP produces a chronic mouse model of PD and serves to elevate concentrations of MPTP in the brain by reducing renal elimination of the toxin [82]. Chronic MPTP/p administration induced primary PD symptoms and neuroinflammation and increased α-syn levels in male C5BL/6 mice [73]. Mice received 10 doses of MPTP (25 mg/kg) in combination with probenecid (250 mg/kg).…”

Restoring Colon Motility in Parkinson's Disease: GDNF-Mediated CX43 Suppression in Reactive Enteric Glial Cells

“…EGCs are pivotal in supporting neural signaling and promoting neuronal survival. In the past, their depletion was considered a potential mechanism underlying enteric neuropathy [7]. However, in the central nervous system (CNS), emerging data suggest that the primary driver of neurodegeneration during neuroin ammation is chronic astrocyte activation, a phenomenon known as reactive gliosis, rather than the loss of glial cells [8].…”