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Link to original content: http://pubmed.ncbi.nlm.nih.gov/35650269/
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Review
. 2022 Jun 1;8(1):66.
doi: 10.1038/s41531-022-00324-9.

Altered neural cell junctions and ion-channels leading to disrupted neuron communication in Parkinson's disease

Saptamita Paul Choudhury #  1 , Sarika Bano #  2 , Srijon Sen #  3 , Kapil Suchal  4 , Saroj Kumar  5   6 , Fredrik Nikolajeff  6 , Sanjay Kumar Dey  7 , Vaibhav Sharma  8
Affiliations
Review

Altered neural cell junctions and ion-channels leading to disrupted neuron communication in Parkinson's disease

Saptamita Paul Choudhury et al. NPJ Parkinsons Dis. .

Abstract

Parkinson's disease (PD) is a neurological disorder that affects the movement of the human body. It is primarily characterized by reduced dopamine levels in the brain. The causative agent of PD is still unclear but it is generally accepted that α-synuclein has a central role to play. It is also known that gap-junctions and associated connexins are complicated structures that play critical roles in nervous system signaling and associated misfunctioning. Thus, our current article emphasizes how, alongside α-synuclein, ion-channels, gap-junctions, and related connexins, all play vital roles in influencing multiple metabolic activities of the brain during PD. It also highlights that ion-channel and gap-junction disruptions, which are primarily mediated by their structural-functional changes and alterations, have a role in PD. Furthermore, we discussed available drugs and advanced therapeutic interventions that target Parkinson's pathogenesis. In conclusion, it warrants creating better treatments for PD patients. Although, dopaminergic replenishment therapy is useful in treating neurological problems, such therapies are, however, unable to control the degeneration that underpins the disease, thereby declining their overall efficacy. This creates an additional challenge and an untapped scope for neurologists to adopt treatments for PD by targeting the ion-channels and gap-junctions, which is well-reviewed in the present article.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Braak-staging of Lewy pathology in PD.
Braak et al., 2003 suggested a six staged course of Parkinson’s illness. As per this concept, α-synuclein accumulates particularly in cerebral areas as well as in neuronal areas, resulting in Lewy pathogenesis throughout a stereo typical, sequential behavior which steps up caudo-rostrally. In its first stage, Lewy pathogenesis starts through the lower midbrain (along with the dorsal motor nucleus of the vagus nerve in the medulla), then to the coeruleus-subcoeruleus complex, raphe nuclei, giganto cellular reticular nucleus in the anteromedial temporal mesocortex, cingulate cortex, and later to the neocortical structures. The illness is thought to initiate in the peripheral and spread to the CNS. With the extent of this Braak stage, the extent of infections in the sensitive areas worsens, and the illness progresses.
Fig. 2
Fig. 2. Different molecular pathways that are involved in the pathogenesis of PD.
Several factors are implicated in the preferential degradation of substantia nigra neurons in the brain during Parkinsonism, involving cytotoxic peptide buildup and aggregation (1), mitochondrial malfunction (2), and oxidative stress. The buildup of α-synuclein is an important phase in pathogenesis which is a component of the Lewy Body. Defects in the Ubiquitin-Proteasome System (3), and Lysosomal autophagy pathway (4), which usually operates as a form of protein degradation system, cause changes in protein regulation, which may encourage the extremely toxic buildup of peptides that are harmful to neurotransmission. Neural cell apoptosis in Parkinsonism is also caused by mitochondrial malfunction, which causes an increase in oxidative stress and a decrease in ATP synthesis. Neuronal malfunction and the buildup of misfolded α-synuclein originate from impairments within protein and membrane trafficking mechanism (5). Similarly, alterations in intracellular sorting and disintegration have a significant impact on the neuronal trafficking of protein aggregates, enabling the cell-to-cell dissemination of dangerous α-synuclein molecules leading to increased pathological alternations in this disease. ER: Endoplasmic Reticulum.
Fig. 3
Fig. 3. Mechanism of neuroinflammation in PD.
Interaction among various cell groups inside the cortex causes inflammation is depicted here. Neurons, astrocytes, microglia, and endothelial cells are vulnerable to α-synuclein aggregation (i.e., through phagocytic cells, endocytic pathway, Toll-like receptor (TLR) activation, etc.), which could indeed hinder their homeostatic operations (diminished secretion of neurotrophic factors (NFs), deficient glutamate uptake, etc.) as well as production of proinflammatory cytokines and chemokines (MHCI in microglial cells, adhesion molecules in the endothelium, etc.). Peripheral immune cells (such as CD4+ T cells) are also drawn into the cerebral tissue. The presence of these immunoregulatory factors, as well as the lack of effective relieving processes, adds to the inflammation milieu. VCAM: Vascular Cell Adhesion Protein, ICAM1: Intercellular Adhesion Molecule 1, NOS: Nitric oxide species, ROS: Reactive Oxygen Species, SASP: Senescence-associated secretory phenotype.
Fig. 4
Fig. 4. Gut-brain microbiome interaction.
Changes inside the intestinal microbiome might encourage α-synuclein accumulation as well as cause an inflammatory reaction inside the periphery. This may include elevated cytokine production and activation of T cells, according to the “gut-brain axis” concept in PD. Aggregation of α-synuclein is thought to propagate in a prion-like way initially from the peripheral to the central nervous system via the vagus nerve. When it enters the brain, proteinopathy, in combination with many invoking variables like mitochondrial impairment, ROS, etc., would then endure core inflammatory response inside a vicious spiral among dropping dead dopamine neuronal cells, glia, and activated endothelium. This will in turn get exacerbated by intruding peripheral immune cells. SCFA: Short-chain fatty acids, VCAM: Vascular Cell Adhesion Molecule, ICAM1: Intercellular Adhesion Molecule 1.
Fig. 5
Fig. 5. Structural organization of connexins and connexons to form gap-junction.
Panel a: Gap-junctions are made up of homomeric or heteromeric hexamers of connexin, connexon (hemichannels) that are situated side by side in the plasma membranes of two neighboring cells. Connexins have four strongly organized transmembrane segments (TMSs), with predominantly unstructured C and N cytosolic termini, a cytoplasmic loop (CL), and two extracellular loops (EL-1) and (EL-2). Connexins create hemichannels, or connexons, within clusters of six, and two hemichannels join to produce gap-junctions. Panel b: The connexin polypeptide crosses across the membranes four times (black), exposing its amino-terminal and carboxy-terminal regions to the cytosol and connecting via two extracellular and one intracellularly exposed loops. The extremely consistent amino-terminal domain (maroon) regulates its channeling pore whereas the two invariant disulfide-linked external loops (magenta) regulate hemichannel coupling among neighboring channels. The length of the cytoplasmic loop (brown) differs widely amongst connexin subclasses. Within the connexin familial member, the span of the cytoplasm terminal (deep green) and its amino acid composition are highly variable.
Fig. 6
Fig. 6. Pictorial depiction showing that connexins can be arranged in many different ways in a gap-junction channel.
The diagram depicts several constituents of the gap-junction channel. A particular kind of connexin forms homomeric connexons. Heteromeric connexons are made up of greater than a single connexin kind. Whenever connexons of a similar structure create a gap-junction channel, it is referred to be a homotypic channel. Whenever the constituents of the connexons vary, the channels are known as heterotypic. Depending on homology, the connexin group is classified into five subgroups (α, β, γ, δ, and ε). Connexins oligomerize into homomeric or heteromeric hexamers alongside adjacent connexins of a similar subtype as well as on rare occasions, with connexins of different subtypes, resulting in a very diverse channel configurations.
Fig. 7
Fig. 7. Pictorial depiction of major changes occurring in the regulation of Cx30, Cx36, and Cx43 in neurons, astrocytes, and microglia, respectively in a PD patient.
SNCA mutation leads to the accumulation of Lewy bodies which in turn increases the opening of Cx43 HCs, thereby resulting in elevated internalized Ca2+ levels and cytokine production. SNCA: Synuclein Alpha gene.
Fig. 8
Fig. 8. Pictorial depiction of different types of ion-channels in the CNS and their mechanism of action under unstressed (Panel a) and stressed (Panel b) conditions.
Panel a: Mechanistic view of networking of ion-channels in SN dopamine nerve cells in PD and other health states. Under physiological conditions, activity-dependent Ca2+ loads due to (1) active participation of LTCC (L-type Calcium Chanel) and VGCC (Voltage-Gated Calcium Channel), with the help of KATP/NMDA-R, which mediates bursting activity and Ca2+-stimulated TCA (Tri Carboxylic Acid) cycle and m-NOS, (2) generated ROS for SN DA, which is controlled by ER (Endoplasmic Reticulum), mitochondrial Ca2+-buffering, UCP, ion-channels that reduces electrical activities like D2-AR/NCS1/GIRK-2, KATP, SK-3, anti-oxidative enzyme kinetics such as DJ1, SOD (Superoxide dismutase) function, and (3) Ca2+ dependent gene expression. Panel b: As the relative level of Ca2+, ROS, NO (Nitric Oxide), and metabolic stress increases, the controlled mechanism may not be enough for altered SN dopamine activity, altered gene expression to remain under physiological regulation thereby leading to apoptosis. TTCC: T-type calcium channel, DJ-1: Mutations in DJ-1 (PARK7), D2R: Dopamine Receptor, ROS: Reactive Oxygen Species, GIRK-2: G-protein-coupled inwardly rectifying potassium (GIRK) channel.
Fig. 9
Fig. 9. Mechanistic view of roles of different K+-channels in the diagnosis and treatment of the PD pathogenesis.
Cellular and animal models of Parkinsonism showed that SK channels, Type-A K+ channels, and Kv-7/ KCNQ channels possess a potential for PD diagnosis. Activators and blockers of these three potassium channels protect the dopaminergic nerve cells in SNc, modulate excitation of nerve cells, influence the release of DA, and attenuate motor symptoms. NMDA N-methyl-D-aspartate receptor, NADPH Nicotinamide adenine dinucleotide phosphate oxidase, MAPK Mitogen-Activated Protein Kinase pathway, GDNF Glial-cell derived neurotrophic factor.
Fig. 10
Fig. 10. Cross connection between α-synuclein-GBA-LRRK2 axis and ion-channels/gap-junctions to develop PD.
This is an example of convergent processes between LRRK2, GBA, and α-synuclein, with both impacting the autophagy-lysosomal system but acting on different targets within the system. CMA and autophagosome formation can be blocked by mutant or aggregated α-synuclein, and mutant LRRK2 can likewise impede CMA, impair mitophagy, and delay autophagosome trafficking. Malfunction in GBA can lead to the production of less active or inactive GCase thereby leading to aggregation of α-synuclein. This LRRK2-GBA-α-synuclein axis can also interfere with diverse neuronal ion-channels and gap-jucntions to PD pathogenesis. CMA Chaperone-mediated autophagy, Lamp2a lysosome-associated membrane protein type 2a, GCase β-glucocerebrosidase, GBA gene encoding GCase.
Fig. 11
Fig. 11. Pictorial depiction of different blockers of ion-channels and gap-jucntions to treat PD.
While DHPs and Safinamide block Ca2+ and Na+ channels, respectively, Amantadine blocks NMDA receptor to treat PD. Similarly, Carbenoxolone (CBX), Octanol, and Gastrodin can block Cx26, Cx38, and Cx43, respectively as a treatment for PD. Trodusquemine can prevent aggregation of α-synuclein and related mutations to prevent Parkinsonism. DHPS Dihydropyridines (DHPs), ROS Reactive Oxygen Species.
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References

    1. Hirsch L, Jette N, Frolkis A, Steeves T, Pringsheim T. The Incidence of Parkinson’s Disease: A Systematic Review and Meta-Analysis. Neuroepidemiology. 2016;46:292–300. doi: 10.1159/000445751. - DOI - PubMed
    1. Lill CM. Genetics of Parkinson’s disease. Mol. Cell. probes. 2016;30:386–396. doi: 10.1016/j.mcp.2016.11.001. - DOI - PubMed
    1. Ball N, Teo W-P, Chandra S, Chapman J. Parkinson’s Disease and the Environment. Front Neurol. 2019;10:218–218. doi: 10.3389/fneur.2019.00218. - DOI - PMC - PubMed
    1. Verstraeten A, Theuns J, Van Broeckhoven C. Progress in unraveling the genetic etiology of Parkinson disease in a genomic era. Trends Genet.: TIG. 2015;31:140–149. doi: 10.1016/j.tig.2015.01.004. - DOI - PubMed
    1. Kalinderi, K., Bostantjopoulou, S. & Fidani, L. The genetic background of Parkinson’s disease: current progress and future prospects. Acta. Neurol. Scand.134, 314–326 (2016). - PubMed