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Genetic Variants in Dopamine Receptors and Neurodegenerative Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (31 October 2020) | Viewed by 16746

Special Issue Editors


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Guest Editor
Center for Research in Medical Pharmacology, University of Insubria, Varese, Italy

E-Mail Website
Guest Editor
Center for Research in Medical Pharmacology, University of Insubria, 21100 Varese, Italy
Interests: neuropharmacology; immunopharmacology; adrenergic transmission; dopaminergic transmission; phytopharmacology

Special Issue Information

Dear Colleagues,

Dopamine (DA) plays a critical role in both common (e.g., Alzheimer’s and Parkinson’s disease (AD and PD, respectively)) and uncommon neurodegenerative diseases (e.g., Prion disease, motor neuron disease, Huntington’s disease, spinocerebellar ataxia, spinal muscular atrophy). DA acts on five different dopaminergic receptors (DR) grouped into two families: The D1-like (D1 and D5) activate and the D2-like (D2, D3, and D4) receptors, which inhibit adenylate cyclase. Several genetic variants, in particular, single nucleotide polymorphisms (SNPs, i.e., DNA sequence variations occurring when a single nucleotide in the genome differs between paired chromosomes), have been described in DR genes (DR). The effects of DR variability have been investigated with regard to both disease susceptibility and clinical features. For example, there are reports documenting increased AD risk for carriers of specific DR SNPs. On the other hand, there is robust evidence showing that DR variations influence not only motor and nonmotor features of PD, but also the phenotype of several psychiatric diseases, such as schizophrenia, bipolar disorder, substance abuse, and addiction. Notwithstanding such acquisitions, significant knowledge gaps need to be bridged to translate basic evidence to clinical applications.

In light of these observations, the genetic variability in DR system represents an interesting target for investigating etiology, disease progression, and drug response in neurodegenerative diseases.

This Special Issue will encompass a selection of original research papers and reviews aimed at highlighting the currently available evidence on genetic variability in DRs and the progression as well as drug therapy response. This will eventually become a reference for those interested in the fields of phenotype variability and pharmacological response in neurodegenerative diseases.

Dr. Marco Ferrari
Prof. Dr. Cristoforo Comi
Prof. Dr. Franca Marino
Guest Editors

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Keywords

  • Dopamine receptors
  • Pharmacogenetics
  • Neurodegenerative diseases
  • Single nucleotide polymorphisms

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Published Papers (2 papers)

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Research

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26 pages, 10490 KiB  
Article
Novel Diels–Alder Type Adducts from Morus alba Root Bark Targeting Human Monoamine Oxidase and Dopaminergic Receptors for the Management of Neurodegenerative Diseases
by Pradeep Paudel, Se Eun Park, Su Hui Seong, Hyun Ah Jung and Jae Sue Choi
Int. J. Mol. Sci. 2019, 20(24), 6232; https://doi.org/10.3390/ijms20246232 - 10 Dec 2019
Cited by 16 | Viewed by 4005
Abstract
In this study, we delineate the human monoamine oxidase (hMAO) inhibitory potential of natural Diels–Alder type adducts, mulberrofuran G (1), kuwanon G (2), and albanol B (3), from Morus alba root bark to characterize their [...] Read more.
In this study, we delineate the human monoamine oxidase (hMAO) inhibitory potential of natural Diels–Alder type adducts, mulberrofuran G (1), kuwanon G (2), and albanol B (3), from Morus alba root bark to characterize their role in Parkinson’s disease (PD) and depression, focusing on their ability to modulate dopaminergic receptors (D1R, D2LR, D3R, and D4R). In hMAO-A inhibition, 13 showed mild effects (50% inhibitory concentration (IC50): 54‒114 μM). However, 1 displayed moderate inhibition of the hMAO-B isozyme (IC50: 18.14 ± 1.06 μM) followed by mild inhibition by 2 (IC50: 57.71 ± 2.12 μM) and 3 (IC50: 90.59 ± 1.72 μM). Our kinetic study characterized the inhibition mode, and the in silico docking predicted that the moderate inhibitor 1 would have the lowest binding energy. Similarly, cell-based G protein-coupled receptors (GPCR) functional assays in vector-transfected cells expressing dopamine (DA) receptors characterized 13 as D1R/D2LR antagonists and D3R/D4R agonists. The half-maximum effective concentration (EC50) of 13 on DA D3R/D4R was 15.13/17.19, 20.18/21.05, and 12.63/‒ µM, respectively. Similarly, 13 inhibited 50% of the DA response on D1R/D2LR by 6.13/2.41, 16.48/31.22, and 7.16/18.42 µM, respectively. A computational study revealed low binding energy for the test ligands. Interactions with residues Asp110, Val111, Tyr365, and Phe345 at the D3R receptor and Asp115 and His414 at the D4R receptor explain the high agonist effect. Likewise, Asp187 at D1R and Asp114 at D2LR play a crucial role in the antagonist effects of the ligand binding. Our overall results depict 13 from M. alba root bark as good inhibitors of hMAO and potent modulators of DA function as D1R/D2LR antagonists and D3R/D4R agonists. These active constituents in M. alba deserve in-depth study for their potential to manage neurodegenerative disorders (NDs), particularly PD and psychosis. Full article
(This article belongs to the Special Issue Genetic Variants in Dopamine Receptors and Neurodegenerative Diseases)
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Review

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23 pages, 2909 KiB  
Review
Roles of the Functional Interaction between Brain Cholinergic and Dopaminergic Systems in the Pathogenesis and Treatment of Schizophrenia and Parkinson’s Disease
by Srijan Acharya and Kyeong-Man Kim
Int. J. Mol. Sci. 2021, 22(9), 4299; https://doi.org/10.3390/ijms22094299 - 21 Apr 2021
Cited by 18 | Viewed by 12059
Abstract
Most physiologic processes in the brain and related diseases involve more than one neurotransmitter system. Thus, elucidation of the interaction between different neurotransmitter systems could allow for better therapeutic approaches to the treatments of related diseases. Dopaminergic (DAergic) and cholinergic neurotransmitter system regulate [...] Read more.
Most physiologic processes in the brain and related diseases involve more than one neurotransmitter system. Thus, elucidation of the interaction between different neurotransmitter systems could allow for better therapeutic approaches to the treatments of related diseases. Dopaminergic (DAergic) and cholinergic neurotransmitter system regulate various brain functions that include cognition, movement, emotion, etc. This review focuses on the interaction between the brain DAergic and cholinergic systems with respect to the pathogenesis and treatment of schizophrenia and Parkinson’s disease (PD). We first discussed the selection of motor plans at the level of basal ganglia, the major DAergic and cholinergic pathways in the brain, and the receptor subtypes involved in the interaction between the two signaling systems. Next, the roles of each signaling system were discussed in the context of the negative symptoms of schizophrenia, with a focus on the α7 nicotinic cholinergic receptor and the dopamine D1 receptor in the prefrontal cortex. In addition, the roles of the nicotinic and dopamine receptors were discussed in the context of regulation of striatal cholinergic interneurons, which play crucial roles in the degeneration of nigrostriatal DAergic neurons and the development of L-DOPA-induced dyskinesia in PD patients. Finally, we discussed the general mechanisms of nicotine-induced protection of DAergic neurons. Full article
(This article belongs to the Special Issue Genetic Variants in Dopamine Receptors and Neurodegenerative Diseases)
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