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Inherited Disorders in Neurotransmitters: A Molecular, Cellular and Systemic Perspective

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 17149

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Special Issue Editors

Dr. Mariarita Bertoldi

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Guest Editor

Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, 37134 Verona, Italy
Interests: aromatic amino acid decarboxylase or dopa decarboxylase; pyridoxal 5’-phosphate; AADC deficiency; molecular and cellular investigations; drug design; bioinformatics; inhibitors
Special Issues, Collections and Topics in MDPI journals

Dr. Patrizia Polverino de Laureto

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Guest Editor

Department of Pharmaceutical Sciences, CRIBI Biotechnology Centre, University of Padova, 30131 Padova, Italy
Interests: neurodegeneration; alpha-synuclein; amyloid fibril formation and inhibition; limited proteolysis; protein structure
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Monoamine neurotransmitters are essential molecules responsible for mediating neuronal transmission. A common feature among these messengers is the fact that they derive from (or are) amino acids. They include catecholamines (dopamine, adrenaline, noradrenaline), indoleamines (serotonin and tryptamine), amino acids (γ-aminobutyric acid (GABA), glycine, aspartate and glutamate) and acetylcholine. They are responsible for disorders such as Parkinson’s and Alzheimer’s disease, depression and other neuropsychiatric diseases in adults. In children, they are involved in the great majority of developmental disorders such as epilepsy, autism, ADHD, learning and intellectual disabilities, and movement disorders. Mutations in the genes coding for enzymes/proteins related to neurotransmitters synthesis, metabolism and transport lead to a variety of inherited deficiencies, globally referred as neurometabolic disorders. Although some markers for the pathological states due to monoamine neurotransmitters lack or alteration are known, other efforts should be done to understand the molecular and cellular causes in order to find more appropriate systemic approaches. This represents a fundamental question to a full understanding that could be the rationale for the development of new drugs.

This Special Issue entitled “Inherited disorders in neurotransmitters: a molecular, cellular and systemic perspective” addresses this research field and is focused on the research of the molecular cause of monoamine neurotransmitters deficiencies. It will include a selection of research papers and reviews about different aspects of monoamine neurotransmitters deficiency, with particular regard on the molecular and cellular level as well as a wider approach of system biology.

Prof. Dr. Mariarita Bertoldi
Prof. Dr. Patrizia Polverino de Laureto
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

monoamine neurotransmitters

inherited disorders

neurometabolic disorders

amino acids

dopamine

serotonin

γ-aminobutyric acid

Published Papers (7 papers)

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Editorial

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2 pages, 165 KiB

Open AccessEditorial

The Integrated Approach to Inherited Disorders in Neurotransmitters from Molecules to Systems

by Mariarita Bertoldi and Patrizia Polverino de Laureto

Int. J. Mol. Sci. 2022, 23(24), 15974; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232415974 - 15 Dec 2022

Viewed by 813

Abstract

This Special Issue focusses on monoamine neurotransmitters responsible for mediating neuronal transmission [...] Full article

(This article belongs to the Special Issue Inherited Disorders in Neurotransmitters: A Molecular, Cellular and Systemic Perspective)

Research

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9 pages, 3971 KiB

Open AccessArticle

Association between Decreased ITGA7 Levels and Increased Muscle α-Synuclein in an MPTP-Induced Mouse Model of Parkinson’s Disease

by Sangeun Han, Sabina Lim and Sujung Yeo

Int. J. Mol. Sci. 2022, 23(10), 5646; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105646 - 18 May 2022

Cited by 3 | Viewed by 1552

Abstract

Parkinson's disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra (SN), reducing dopaminergic levels in the striatum and affecting motor control. Herein, we investigated the potential relationship between integrin α7 (ITGA7) and α-synuclein (α-syn) in the muscle of methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-induced mice and C2C12 cells. To characterize the pathology of PD, we examined the expression of tyrosine hydroxylase (TH) in the SN of the midbrain. Compared with the control group, MPTP-treated mice showed a significant decrease in TH expression in the SN, accompanied by a significant decrease in muscle ITGA7 expression. Compared with the control group, α-syn expression was increased in the MPTP group. Furthermore, the pattern of α-syn expression in the MPTP group was similar to the ITGA7 expression pattern in the control group (linear forms). To determine the relationship between ITGA7 and PD, we examined the expression of ITGA7 and α-syn after ITGA7 knockdown using siRNA in C2C12 cells. ITGA7 expression significantly decreased while α-syn expression significantly increased in siRNA-treated C2C12 cells. These results suggest that decreased ITGA7 muscle expression could increase α-syn expression. Moreover, α-syn accumulation, induced by decreased muscle ITGA7, might contribute to PD pathology. Full article

(This article belongs to the Special Issue Inherited Disorders in Neurotransmitters: A Molecular, Cellular and Systemic Perspective)

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17 pages, 3413 KiB

Open AccessArticle

CK2 Phosphorylation Is Required for Regulation of Syntaxin 1A Activity in Ca²⁺-Triggered Release in Neuroendocrine Cells

by Noa Barak-Broner, Dafna Singer-Lahat, Dodo Chikvashvili and Ilana Lotan

Int. J. Mol. Sci. 2021, 22(24), 13556; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222413556 - 17 Dec 2021

Cited by 3 | Viewed by 2326

Abstract

The polybasic juxtamembrane region (5RK) of the plasma membrane neuronal SNARE, syntaxin1A (Syx), was previously shown by us to act as a fusion clamp in PC12 cells, as charge neutralization of 5RK promotes spontaneous and inhibits Ca²⁺-triggered release. Using a Syx-based FRET probe (CSYS), we demonstrated that 5RK is required for a depolarization-induced Ca⁺²-dependent opening (close-to-open transition; CDO) of Syx, which involves the vesicular SNARE synaptobrevin2 and occurs concomitantly with Ca²⁺-triggered release. Here, we investigated the mechanism underlying the CDO requirement for 5RK and identified phosphorylation of Syx at Ser-14 (S14) by casein kinase 2 (CK2) as a crucial molecular determinant. Thus, following biochemical verification that both endogenous Syx and CSYS are constitutively S14 phosphorylated in PC12 cells, dynamic FRET analysis of phospho-null and phospho-mimetic mutants of CSYS and the use of a CK2 inhibitor revealed that the S14 phosphorylation confers the CDO requirement for 5RK. In accord, amperometric analysis of catecholamine release revealed that the phospho-null mutant does not support Ca²⁺-triggered release. These results identify a functionally important CK2 phosphorylation of Syx that is required for the 5RK-regulation of CDO and for concomitant Ca²⁺-triggered release. Further, also spontaneous release, conferred by charge neutralization of 5RK, was abolished in the phospho-null mutant. Full article

(This article belongs to the Special Issue Inherited Disorders in Neurotransmitters: A Molecular, Cellular and Systemic Perspective)

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10 pages, 3706 KiB

Open AccessArticle

Decrease in ITGA7 Levels Is Associated with an Increase in α-Synuclein Levels in an MPTP-Induced Parkinson’s Disease Mouse Model and SH-SY5Y Cells

by Sangeun Han, Min Hyung Seo, Sabina Lim and Sujung Yeo

Int. J. Mol. Sci. 2021, 22(23), 12616; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222312616 - 23 Nov 2021

Cited by 4 | Viewed by 2268

Abstract

We investigated the potential association between integrin α7 (ITGA7) and alpha-synuclein (α-syn) in a methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson’s disease (PD) mouse model. Tyrosine hydroxylase (TH), ITGA7, and α-syn expression in the substantia nigra (SN) of the brain were observed to examine the pathological characteristics of PD. To determine the relationship between ITGA7 and PD, the expression of TH and α-syn was investigated after ITGA7 siRNA knockdown in SH-SY5Y cells. The ITGA7 microarray signal was decreased in the SN of the MPTP group, indicating reduced ITGA7 expression compared to that in the control. The expression patterns of ITGA7 in the control group and those of α-syn in the MPTP group were similar on immunohistochemical staining. Reduction in ITGA7 expression by ITGA7 siRNA administration induced a decrease in TH expression and an increase in α-syn expression in SH-SY5Y cells. The decreased expression of ITGA7 significantly decreased the expression of bcl2 and increased the bax/bcl2 ratio in SH-SY5Y cells. These results suggest that reduced ITGA7 expression may be related to increased α-syn expression and apoptosis of dopaminergic cells in an MPTP-induced PD mouse model. To the best of our knowledge, this is the first study to show an association between ITGA7 and PD. Full article

(This article belongs to the Special Issue Inherited Disorders in Neurotransmitters: A Molecular, Cellular and Systemic Perspective)

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25 pages, 10826 KiB

Open AccessArticle

Insertion of Calcium-Permeable AMPA Receptors during Epileptiform Activity In Vitro Modulates Excitability of Principal Neurons in the Rat Entorhinal Cortex

by Dmitry V. Amakhin, Elena B. Soboleva, Anton V. Chizhov and Aleksey V. Zaitsev

Int. J. Mol. Sci. 2021, 22(22), 12174; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212174 - 10 Nov 2021

Cited by 4 | Viewed by 2141

Abstract

Epileptic activity leads to rapid insertion of calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (CP-AMPARs) into the synapses of cortical and hippocampal glutamatergic neurons, which generally do not express them. The physiological significance of this process is not yet fully understood; however, it is usually assumed to be a pathological process that augments epileptic activity. Using whole-cell patch-clamp recordings in rat entorhinal cortex slices, we demonstrate that the timing of epileptiform discharges, induced by 4-aminopyridine and gabazine, is determined by the shunting effect of Ca²⁺-dependent slow conductance, mediated predominantly by K⁺-channels. The blockade of CP-AMPARs by IEM-1460 eliminates this extra conductance and consequently increases the rate of discharge generation. The blockade of NMDARs reduced the additional conductance to a lesser extent than the blockade of CP-AMPARs, indicating that CP-AMPARs are a more significant source of intracellular Ca²⁺. The study’s main findings were implemented in a mathematical model, which reproduces the shunting effect of activity-dependent conductance on the generation of discharges. The obtained results suggest that the expression of CP-AMPARs in principal neurons reduces the discharge generation rate and may be considered as a protective mechanism. Full article

(This article belongs to the Special Issue Inherited Disorders in Neurotransmitters: A Molecular, Cellular and Systemic Perspective)

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9 pages, 4114 KiB

Open AccessArticle

Srpk3 Decrease Associated with Alpha-Synuclein Increase in Muscles of MPTP-Induced Parkinson’s Disease Mice

by Min Hyung Seo and Sujung Yeo

Int. J. Mol. Sci. 2021, 22(17), 9375; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179375 - 29 Aug 2021

Cited by 3 | Viewed by 2283

Abstract

Parkinson’s disease (PD) is characterized by a loss of dopaminergic cells in the substantia nigra, and its histopathological features include the presence of fibrillar aggregates of α-synuclein (α-syn), which are called Lewy bodies and Lewy neurites. Lewy pathology has been identified not only in the brain but also in various tissues, including muscles. This study aimed to investigate the link between serine/arginine-rich protein specific kinase 3 (srpk3) and α-syn in muscles in PD. We conducted experiments on the quadriceps femoris of a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model and the C2C12 cell line after treatment with 1-methyl-4-phenylpyridinium (MPP+) and srpk3 short interfering RNA (siRNA). Compared to the control group, the MPTP group showed significantly reduced expression of srpk3, but increased expression of α-syn. In MPP+-treated C2C12 cells, srpk3 expression gradually decreased and α-syn expression increased with the increasing MPP+ concentration. Moreover, experiments in C2C12 cells using srpk3 siRNA showed increased expressions of α-syn and phosphorylated α-syn. Our results showed that srpk3 expression could be altered by MPTP intoxication in muscles, and this change may be related to changes in α-syn expression. Furthermore, this study could contribute to advancement of research on the mechanism by which srpk3 plays a role in PD. Full article

(This article belongs to the Special Issue Inherited Disorders in Neurotransmitters: A Molecular, Cellular and Systemic Perspective)

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Review

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15 pages, 2831 KiB

Open AccessReview

Aromatic Amino Acid Decarboxylase Deficiency: The Added Value of Biochemistry

by Riccardo Montioli and Carla Borri Voltattorni

Int. J. Mol. Sci. 2021, 22(6), 3146; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22063146 - 19 Mar 2021

Cited by 18 | Viewed by 4917

Abstract

Aromatic amino acid decarboxylase (AADC) deficiency is a rare, autosomal recessive neurometabolic disorder caused by mutations in the DDC gene, leading to a deficit of AADC, a pyridoxal 5′-phosphate requiring enzyme that catalyzes the decarboxylation of L-Dopa and L-5-hydroxytryptophan in dopamine and serotonin, respectively. Although clinical and genetic studies have given the major contribution to the diagnosis and therapy of AADC deficiency, biochemical investigations have also helped the comprehension of this disorder at a molecular level. Here, we reported the steps leading to the elucidation of the functional and structural features of the enzyme that were useful to identify the different molecular defects caused by the mutations, either in homozygosis or in heterozygosis, associated with AADC deficiency. By revisiting the biochemical data available on the characterization of the pathogenic variants in the purified recombinant form, and interpreting them on the basis of the structure-function relationship of AADC, it was possible: (i) to define the enzymatic phenotype of patients harboring pathogenic mutations and at the same time to propose specific therapeutic managements, and (ii) to identify residues and/or regions of the enzyme relevant for catalysis and/or folding of AADC. Full article

(This article belongs to the Special Issue Inherited Disorders in Neurotransmitters: A Molecular, Cellular and Systemic Perspective)

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