From the Gut to the Brain: The Role of Enteric Glial Cells and Their Involvement in the Pathogenesis of Parkinson’s Disease
Abstract
:1. Introduction: Braak’s Hypothesis and the Enteric Nervous System
1.1. Parkinson’s Disease
1.2. Parkinson’s Disease and the Gastrointestinal Tract
1.3. The Enteric Nervous System
2. Methods
3. Enteric Glial Cells
3.1. Types of Enteric Glia
3.2. Enteric Glial Markers
3.3. Functions of the Enteric Glia and Their Role in Disease
4. Parkinson’s Disease and Enteric Glia
4.1. Studies Using Animal Models and Cell Cultures
4.1.1. Rotenone and Other Pesticides
4.1.2. MTPT1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
4.1.3. 6-Hydroxydopamine (6-OHA)
4.1.4. Adeno-Associated Virus (AAV)-α-Synuclein
4.1.5. A53 α-Synuclein Mouse Model
4.2. Studies Using Human Biopsies from PD Patients
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Correction Statement
Abbreviations
4-HNE | 4-hydroxynonenal |
6-OHDA | 6-hydroxydopamine |
α-syn | α-synuclein |
AVV | adeno-associated virus |
CA | caffeic acid |
CD | Crohn’s disease |
CGA | chlorogenic acid |
CNS | central nervous system |
EGCs | enteric glial cells |
ENS | enteric nervous system |
GDNF | glial-derived neurotrophic factor |
GFAP | glial fibrillary acidic protein |
GI | gastrointestinal |
IEB | intestinal epithelial barrier |
IBD | inflammatory bowel disease |
IBS | irritable bowel syndrome |
IL | interleukin |
iNOS | inducible nitric oxide synthase |
IR | immunoreactivity, immunoreactive |
KO | knockout |
LC3 | microtubule-associated protein 1A/1B-light chain 3 |
LRRK2 | leucine-rich repeat kinase 2 |
LPS | lipopolysaccharide |
MPTP | 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine |
MPTP/p | MPTP/probenecid |
MTs | metallothioneins |
NAD | nicotine adenine dinucleotide |
PD | Parkinson’s disease |
p-α-syn | Phosphorylated alpha-synuclein |
PPAR | proliferator activated receptor |
PLP1 | proteolipid protein 1 |
S100β | calcium binding protein B |
TDO | tryptophan 2,3-dioxygenase |
TNF-α | tumor necrosis factor-alpha |
TLR | Toll-like receptors |
UC | ulcerative colitis |
WT | wild type |
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Type | Subtype | Location | Functions |
---|---|---|---|
Intraganglionar | Myenteric type I | Small and extended star-shaped cells that surround the neurons in the myenteric ganglia | Modulation of enteric neuron activity |
Oxidative stress regulation | |||
Trophic support | |||
Neuroinflammation regulation | |||
Gliogenesis | |||
Neurogenesis | |||
Mucosal glia replenishment | |||
Submucosal type I | Associated with neurons within submucosal ganglia | Modulation of secretory neuron activity | |
Extraganglionar | Interganglionar type II | Located in the interganglionic fiber tracts | They propagate the signal in the glial network |
Mucosa type III | Some follow nerve fibers, while others terminate in the mucosal epithelium | Influence the maturation of epithelial cells | |
Potentially modulate immune responses Identification from postnatal development | |||
Myenteric plexus/submucosal plexus type III | Located in the extraganglionic regions at the level of the myenteric and submucosal plexuses | Unknown | |
Intramuscular type IV | Associated with nerve fibers in the circular and longitudinal muscle layers of smooth muscles | Unknown |
Type | Characteristics | Mechanisms of Action |
---|---|---|
Activated | Controls the activity of surrounding cells | The enteric glial activation encoded by intracellular Ca2+ responses modulate enteric excitatory motor and secretomotor neurocircuits |
Exerts beneficial homeostatic effects | ||
Responds to physiological stimuli | ||
Reactive | Responds to physiopathological disturbances of any severity | Responds to intestinal inflammation. |
Contributes to neuronal death during acute intestinal inflammation | ||
Changes can alter glial activities through gain or loss of functions, which can be beneficial or detrimental | Contributes to vagal anti-inflammatory effects on resident intestinal immune cells after intestinal injury | |
Dysfunctional | Dysfunctional or maladaptive response of glial cells | Altered enteric glial networks, displaying dysfunctional responses in patients with different GI disorders, including IBD, immunological disorders of the gut or PD |
Exerts harmful effects contributing to a disease, in addition to being permanent |
Marker | Characteristics | Functions |
---|---|---|
Nuclear transcription factor (Sox-10) | Key to the development of the neuronal crest cells and the enteric glia | Crucial role in neuronal crest cells and peripheral glia differentiation and maintenance |
Specific marker for EGCs progenitors | Controls and modulates the expression of several key genes for early ENS development | |
Found in glial precursors and in most of the mature and immature EGCs | Promotes the expression of various transcription factors crucial for neuronal differentiation, such as Phox2b and Ascl1 | |
Glial fibrillary acidic protein (GFAP) | It is found along neuronal plexuses. | There is an increased GFAP intensity when the tissue is inflamed or next to colonic cancer |
Does not occur prenatally | ||
All subtypes of enteric glia within the mouse ileum express GFAP, but at different levels. | ||
Dynamic expression that varies depending on the glial state | ||
GFAPκ is the main isoform in colonic EGCs relative to GFAPα and GFAPδ | ||
Calcium-binding protein (S100β) | Expressed by both progenitors and differentiated enteric glial cells | Among other functions, this protein contributes to structural support and regulation of the immune response |
Proteolipid protein 1 (PLP1) | In adult mice, it is expressed in both ENS plexuses, in both, the small and large intestine | Unknown |
PD Induction | Animal | Findings | Ref |
---|---|---|---|
Rotenone | C57BL mice | Increased MT levels. | [65] |
EGCs activation (GFAP-positive) | |||
MT KO mice | Severe myenteric neuronal damage | [65] | |
Reduced EGCs activation | |||
Aggravation of lipid peroxidation | |||
C57BL mice | Increased GFAP-IR in the myenteric plexus | [66] | |
Activated EGCs before neurodegeneration in the CNS | |||
Lack of activation of EGCs at early stages | |||
C57BL mice | No MT presence in the intestine of mice | [67] | |
Cell cultures | CA or CGA prevented rotenone-induced downregulation of MT in cultured cells | ||
C57BL mice Cell cultures | Increased GFAP staining in the myenteric plexus | [68] | |
Impaired mitochondrial bioenergetics | |||
Activation of inflammatory pathways | |||
C57BL/6J mice | TLR4-mediated gut inflammation | [55] | |
TLR4-knockout mice | GFAP staining was unaffected by rotenone administration | ||
C57BL Mice | Restraint stress exacerbated rotenone-induced activation of EGCs | [69] | |
C57BL/6NCrl mice | A TDO inhibitor decreased rotenone-induced labelling of GFAP | [70] | |
MPTP and MPTP/p | Macaca mulatta | No differences in the number/phenotype of Sox-10 IR EGCs | [71] |
EGCs are not a primary target of MPTP in the ENS | |||
The ratio of EGC to neurons was decreased by MPTP | |||
Less protection of myenteric neurons | |||
Marmoset | EGCs IR to Sox-10 were increased | [72] | |
MPTP treatment led to inflammation of the ileum | |||
C5BL/6 mice | Chronic MPTP/p increased aggregated and nitrated α-syn in GFAP-IR EGCs | [73] | |
Acute, elevated 4-HNE in the EGCs after 3 h | |||
EGCs could be initial contributors to synucleinopathies in the stomach | |||
6-OHDA | Sprague-Dawley rats | GFAP IR of EGCs was increased | [74] |
Sprague-Dawley rats | Density of S100β IR EGCs was increased | [75] | |
Nigrostriatal neurodegeneration leads to an increased presence of EGCs in the mucosa | |||
C57BL/6 male mice | Dual response of EGCs: can promote inflammation or intestinal tissue protection | [76] | |
Virus AVV | Sprague-Dawley rats | No changes in EGCs in the ileal submucosal plexus | [77] |
Increase in glial number in the myenteric plexus | |||
Voluntary running protected from increased EGCs | |||
A53 α-syn mouse model | Mutant mice expressing human A53T | Increased GFAP IR EGCs in the mucosa, submucosa and myenteric plexus at 3 months of age | [78] |
Co-localization of GFAP-IR EGCs and TLR2 IR |
Number of Samples | Samples | Findings | Refs |
---|---|---|---|
Control and PD patients (2 samples each) | Ascending Colon | GFAP and Sox-10 were significantly elevated | [63] |
No significant changes in the S100β marker | |||
Levels of glial markers are negatively correlated with disease duration | |||
24 PD, 6 progressive supranuclear palsy and 6 multiple system atrophy patients | Colonic biopsies | Hypophosphorylation of GFAP in EGCs during PD | [86] |
GFAPκ was the major isoform in colonic EGCs | |||
19 asymptomatic PD patients | Colonic biopsies | Increase in S100β-positive glial cells | [87] |
Activation of enteric glial cells | |||
Abnormal tissue repair with development of fibrosis in the mucosa of PD patients | |||
128 patients with PD | Serum | GDNF may act as a protective factor in the prevention of constipation | [88] |
Reduction in GDNF affects the integrity of intestinal mucosal barrier | |||
16 Lewy’s body, 12 non-Lewy’s body disorders cases | Colonic biopsies | Enteric glial cells express LRRK2 | [89] |
EGC-expressed LRRK2 could participate in the modulation of intestinal α-syn aggregation and inflammation in the gut | |||
18 patients with advanced PD, 4 untreated patients with early PD | Duodenal biopsies | Increased size and density of GFAP-positive EGCs suggesting reactive gliosis | [90] |
No colocalization between markers α-syn-5G4 and GFAP antibodies |
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Montalbán-Rodríguez, A.; Abalo, R.; López-Gómez, L. From the Gut to the Brain: The Role of Enteric Glial Cells and Their Involvement in the Pathogenesis of Parkinson’s Disease. Int. J. Mol. Sci. 2024, 25, 1294. https://doi.org/10.3390/ijms25021294
Montalbán-Rodríguez A, Abalo R, López-Gómez L. From the Gut to the Brain: The Role of Enteric Glial Cells and Their Involvement in the Pathogenesis of Parkinson’s Disease. International Journal of Molecular Sciences. 2024; 25(2):1294. https://doi.org/10.3390/ijms25021294
Chicago/Turabian StyleMontalbán-Rodríguez, Alba, Raquel Abalo, and Laura López-Gómez. 2024. "From the Gut to the Brain: The Role of Enteric Glial Cells and Their Involvement in the Pathogenesis of Parkinson’s Disease" International Journal of Molecular Sciences 25, no. 2: 1294. https://doi.org/10.3390/ijms25021294