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Molecular Mechanisms of Neurological and Psychiatric Disease: A Decade of Progress

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 (20 March 2025) | Viewed by 14219

Special Issue Editor

Dr. Giuseppina Martella

E-Mail Website
Guest Editor
1. Laboratory of Neurophysiology and Plasticity, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy
2. Department of Human Sciences, Faculty of Humanities Educations and Sports, Pegaso University, 80143 Naples, Italy
Interests: pathophysiology; movement disorders; motor memory; motor dysfunction; synaptic plasticity; brain circuitry; basal ganglia; striatum (putamen); medium spiny neurons; mitochondria; neurologic and psychiatric disorders; protein synthesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Until several decades ago, psychological and behavioural interventions were the primary treatments for mental health disorders.

Thanks to modern psychopharmacology, medications are accepted to treat more psychiatric disorders.

Unfortunately, the mechanism behind many medications is unknown. Several therapeutic approaches are derived from neurological pathologies.

Psychiatric disorders are often present in various neurological diseases like Alzheimer's and Parkinson's disease, epilepsy, migraine, essential tremors, and stroke. Depression, anxiety disorders, and cognitive impairment are the most common comorbid diagnoses in neurological diseases. It is important to note that comorbidities are frequently overlooked due to common neurochemical mechanisms or a loss of previous functioning levels.

Moreover, some medications may have drawbacks, including drug interactions, side effects, and low effectiveness. In light of these, evidence has become essential to characterize the molecular mechanism of neurological and psychiatric disease to ensure the best treatments are utilized.

The colossal effort of researchers to increase the knowledge of many psychiatric and neurological disorders in the last few decades has helped us to understand not only the developmental stages of many diseases but, principally, the mechanism of action of medication on specific molecular targets.

This Special Issue aims to collect original research articles (regular and rapid communication) and reviews on the underlying molecular mechanisms of psychiatric and degenerative diseases and the therapeutic properties of substances, including those derived from plants.

Dr. Martina Montanari (martimonty@gmail.com) is the Guest Editor Assistant of this Special Issue. Please feel free to contact us or Ms. Martina Montanari for details about the issue.

Dr. Giuseppina Martella
Guest Editor

Manuscript Submission Information

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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

  • Alzheimer's and Parkinson's diseases
  • epilepsy
  • migraine
  • essential tremors
  • stroke
  • depression
  • anxiety disorders
  • cognitive impairment

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Published Papers (7 papers)

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Research

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11 pages, 749 KiB  
Article
Association Between Common Variants in the LAG3/CD4 Genes and Risk for Essential Tremor
by José A. G. Agúndez, Yolanda Macías, Hortensia Alonso-Navarro, Elena García-Martín, Ignacio Álvarez, Pau Pastor, Julián Benito-León, Tomás López-Alburquerque and Félix Javier Jiménez-Jiménez
Int. J. Mol. Sci. 2024, 25(24), 13403; https://doi.org/10.3390/ijms252413403 - 13 Dec 2024
Viewed by 817
Abstract
Many clinical, neuroimaging, neuropathological, epidemiological, and genetic data suggest a relationship between essential tremor (ET) and Parkinson’s disease (PD). Several hypothesis-based gene association studies attempted to find a genetic association between these diseases. Recent case–control association studies in Chinese and Spanish populations showed [...] Read more.
Many clinical, neuroimaging, neuropathological, epidemiological, and genetic data suggest a relationship between essential tremor (ET) and Parkinson’s disease (PD). Several hypothesis-based gene association studies attempted to find a genetic association between these diseases. Recent case–control association studies in Chinese and Spanish populations showed a marginal association between the CD4 rs1922452 and CD4 rs951818 single nucleotide variants (SNVs) and the risk of PD. The proteins encoded by the CD4 and LAG3 genes have an important role in modulating inflammatory responses, and some recent data associated inflammatory markers to ET. This study investigates a possible association between the most common SNVs in the LAG3/CD4 genes and the risk of ET in the Spanish Caucasian population. We genotyped 267 patients diagnosed with familial ET and 270 age- and sex-matched controls using specific TaqMan assays for CD4 rs1922452, CD4 rs951818, and LAG3 rs870849 variants. We found a decreased risk for ET in carriers of the LAG3 rs870849 C/C genotype and the LAG3 rs870849C allelic variant exclusively in men. The mean age of onset of ET was not related to any of the variants studied. These data suggest no association of the gene variants studied with the overall risk for ET, except for a slight decrease in risk in male ET patients carrying the variant LAG3 rs870849C. However, such an association lost significance after correcting for multiple comparisons. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Neurological and Psychiatric Disease: A Decade of Progress)
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21 pages, 4134 KiB  
Article
Small Molecules Inducing Autophagic Degradation of Expanded Polyglutamine Protein through Interaction with Both Mutant ATXN3 and LC3
by Te-Hsien Lin, Wan-Ling Chen, Shao-Fan Hsu, I-Cheng Chen, Chih-Hsin Lin, Kuo-Hsuan Chang, Yih-Ru Wu, Yi-Ru Chen, Ching-Fa Yao, Wenwei Lin, Guey-Jen Lee-Chen and Chiung-Mei Chen
Int. J. Mol. Sci. 2024, 25(19), 10707; https://doi.org/10.3390/ijms251910707 - 4 Oct 2024
Viewed by 1436
Abstract
Polyglutamine (polyQ)-mediated spinocerebellar ataxia (SCA), including SCA1, 2, 3, 6, 7, and 17, are caused by mutant genes with expanded CAG repeats, leading to the intracellular accumulation of aggregated proteins, the production of reactive oxygen species, and cell death. Among SCA, SCA3 is [...] Read more.
Polyglutamine (polyQ)-mediated spinocerebellar ataxia (SCA), including SCA1, 2, 3, 6, 7, and 17, are caused by mutant genes with expanded CAG repeats, leading to the intracellular accumulation of aggregated proteins, the production of reactive oxygen species, and cell death. Among SCA, SCA3 is caused by a mutation in the ATXN3 (ataxin-3) gene. In a circumstance of polyQ aggregation, the autophagic pathway is induced to degrade the aggregated proteins, thereby suppressing downstream deleterious effects and promoting neuronal survival. In this study, we tested the effects of synthetic indole (NC009-1, -2, -3, -6) and coumarin (LM-022, -031) derivatives as chemical chaperones to assist mutant ATXN3-Q75 folding, as well as autophagy inducers to clear aggregated protein. Among the tested compounds, NC009-1, -2, and -6 and LM-031 interfered with Escherichia coli-derived ATXN3-Q75 aggregation in thioflavin T binding and filter trap assays. In SH-SY5Y cells expressing GFP-fused ATXN3-Q75, these compounds displayed aggregation-inhibitory and neurite growth-promoting potentials compared to untreated cells. Furthermore, these compounds activated autophagy by increasing the phosphatidylethanolamine-conjugated LC3 (microtubule associated protein 1 light chain 3)-II:cytosolic LC3-I ratio in these cells. A biochemical co-immunoprecipitation assay by using a mixture of HEK 293T cell lysates containing recombinant ATXN3-Q75-Venus-C-terminus (VC) or Venus-N-terminus (VN)-LC3 protein indicated that NC009-1 and -2 and LM-031 served as an autophagosome-tethering compound (ATTEC) to interact with ATXN3-Q75 and LC3, and the interaction was further confirmed by bimolecular fluorescence complementation analysis in cells co-expressing both ATXN3-Q75-VC and VN-LC3 proteins. The study results suggest the potential of NC009-1 and -2 and LM-031 as an ATTEC in treating SCA3 and, probably, other polyQ diseases. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Neurological and Psychiatric Disease: A Decade of Progress)
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16 pages, 2458 KiB  
Article
Urine 5-Hydroxyindoleacetic Acid Negatively Correlates with Migraine Occurrence and Characteristics in the Interictal Phase of Episodic Migraine
by Michal Fila, Jan Chojnacki, Marcin Derwich, Cezary Chojnacki, Elzbieta Pawlowska and Janusz Blasiak
Int. J. Mol. Sci. 2024, 25(10), 5471; https://doi.org/10.3390/ijms25105471 - 17 May 2024
Cited by 2 | Viewed by 1296
Abstract
Although migraine belongs to the main causes of disability worldwide, the mechanisms of its pathogenesis are poorly known. As migraine diagnosis is based on the subjective assessment of symptoms, there is a need to establish objective auxiliary markers to support clinical diagnosis. Tryptophan [...] Read more.
Although migraine belongs to the main causes of disability worldwide, the mechanisms of its pathogenesis are poorly known. As migraine diagnosis is based on the subjective assessment of symptoms, there is a need to establish objective auxiliary markers to support clinical diagnosis. Tryptophan (TRP) metabolism has been associated with the pathogenesis of neurological and psychiatric disorders. In the present work, we investigated an association between migraine and the urine concentration of TRP and its metabolites 5-hydroxyindoleacetic acid (5-HIAA), kynurenine (KYN), kynurenic acid (KYNA) and quinolinic acid (QA) in 21 low-frequency episodic migraine patients and 32 controls. We chose the interictal phase as the episodic migraine patients were recruited from the outpatient clinic and had monthly migraine days as low as 1–2 in many cases. Migraine patients displayed lower urinary levels of 5-HIAA (p < 0.01) and KYNA (p < 0.05), but KYN and QA were enhanced, as compared with the controls (p < 0.05 and 0.001, respectively). Consequently, the patients were characterized by different values of the 5-HIAA/TRP, KYN/TRP, KYNA/KYN, and KYNA/QA ratios (p < 0.001 for all). Furthermore, urinary concentration of 5-HIAA was negatively correlated with Migraine Disability Assessment score and monthly migraine and monthly headache days. There was a negative correlation between Patient Health Questionnaire 9 scores assessing depression. In conclusion, the urinary 5-HIAA level may be further explored to assess its suitability as an easy-to-determine marker of migraine. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Neurological and Psychiatric Disease: A Decade of Progress)
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19 pages, 6144 KiB  
Article
Differences in Neuropathology between Nitroglycerin-Induced Mouse Models of Episodic and Chronic Migraine
by Songyi Park, Harry Jung, Sang-Won Han, Sang-Hwa Lee and Jong-Hee Sohn
Int. J. Mol. Sci. 2024, 25(7), 3706; https://doi.org/10.3390/ijms25073706 - 26 Mar 2024
Cited by 6 | Viewed by 2155
Abstract
Multiple animal models of migraine have been used to develop new therapies. Understanding the transition from episodic (EM) to chronic migraine (CM) is crucial. We established models mimicking EM and CM pain and assessed neuropathological differences. EM and CM models were induced with [...] Read more.
Multiple animal models of migraine have been used to develop new therapies. Understanding the transition from episodic (EM) to chronic migraine (CM) is crucial. We established models mimicking EM and CM pain and assessed neuropathological differences. EM and CM models were induced with single NTG or multiple injections over 9 days. Mechanical hypersensitivity was assessed. Immunofluorescence utilized c-Fos, NeuN, and Iba1. Proinflammatory and anti-inflammatory markers were analyzed. Neuropeptides (CGRP, VIP, PACAP, and substance P) were assessed. Mechanical thresholds were similar. Notable neuropathological distinctions were observed in Sp5C and ACC. ACC showed increased c-Fos and NeuN expression in CM (p < 0.001) and unchanged in EM. Sp5C had higher c-Fos and NeuN expression in EM (p < 0.001). Iba1 was upregulated in Sp5C of EM and ACC of CM (p < 0.001). Proinflammatory markers were strongly expressed in Sp5C of EM and ACC of CM. CGRP expression was elevated in both regions and was higher in CM. VIP exhibited higher levels in the Sp5C of EM and ACC of CM, whereas PACAP and substance P were expressed in the Sp5C in both models. Despite similar thresholds, distinctive neuropathological differences in Sp5C and ACC between EM and CM models suggest a role in the EM to CM transformation. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Neurological and Psychiatric Disease: A Decade of Progress)
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Review

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37 pages, 574 KiB  
Review
Exceeding the Limits with Nutraceuticals: Looking Towards Parkinson’s Disease and Frailty
by Martina Montanari, Nicola Biagio Mercuri and Giuseppina Martella
Int. J. Mol. Sci. 2025, 26(1), 122; https://doi.org/10.3390/ijms26010122 - 26 Dec 2024
Cited by 1 | Viewed by 1548
Abstract
One of the most pressing challenges facing society today is the rising prevalence of physical and cognitive frailty. This geriatric condition makes older adults more vulnerable to disability, illness, and a heightened risk of mortality. In this scenario, Parkinson’s disease (PD) and geriatric [...] Read more.
One of the most pressing challenges facing society today is the rising prevalence of physical and cognitive frailty. This geriatric condition makes older adults more vulnerable to disability, illness, and a heightened risk of mortality. In this scenario, Parkinson’s disease (PD) and geriatric frailty, which share several common characteristics, are becoming increasingly prevalent worldwide, underscoring the urgent need for innovative strategies. Nutraceuticals are naturally occurring bioactive compounds contained in foods, offering health benefits over and above essential nutrition. By examining the literature from the past decade, this review highlights how nutraceuticals can act as complementary therapies, addressing key processes, such as oxidative stress, inflammation, and neuroprotection. Notably, the antioxidant action of nutraceuticals appears particularly beneficial in regard to PD and geriatric frailty. For instance, antioxidant-rich nutraceuticals may mitigate the oxidative damage linked to levodopa therapy in PD, potentially reducing the side effects and enhancing treatment sustainability. Similarly, the antioxidant effects of nutraceuticals may amplify the benefits of physical activity, enhancing muscle function, cognitive health, and resilience, thereby reducing the risk of frailty. This review proposes a holistic approach integrating nutraceuticals with exercise, pharmacotherapy, and lifestyle adjustments. It promises to transform the management of ARD, prolong life, and improve the quality of life and well-being of older people. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Neurological and Psychiatric Disease: A Decade of Progress)
35 pages, 549 KiB  
Review
Trace Elements Levels in Major Depressive Disorder—Evaluation of Potential Threats and Possible Therapeutic Approaches
by Jacek Baj, Julia Bargieł, Justyna Cabaj, Bartosz Skierkowski, Gabriela Hunek, Piero Portincasa, Jolanta Flieger and Agata Smoleń
Int. J. Mol. Sci. 2023, 24(20), 15071; https://doi.org/10.3390/ijms242015071 - 11 Oct 2023
Cited by 18 | Viewed by 3965
Abstract
The multifactorial etiology of major depressive disorder (MDD) includes biological, environmental, genetic, and psychological aspects. Recently, there has been an increasing interest in metallomic studies in psychiatry, aiming to evaluate the role of chosen trace elements in the MDD etiology as well as [...] Read more.
The multifactorial etiology of major depressive disorder (MDD) includes biological, environmental, genetic, and psychological aspects. Recently, there has been an increasing interest in metallomic studies in psychiatry, aiming to evaluate the role of chosen trace elements in the MDD etiology as well as the progression of symptoms. This narrative review aims to summarize the available literature on the relationship between the concentration of chosen elements in the serum of patients with MDD and the onset and progression of this psychiatric condition. The authors reviewed PubMed, Web of Science, and Scopus databases searching for elements that had been investigated so far and further evaluated them in this paper. Ultimately, 15 elements were evaluated, namely, zinc, magnesium, selenium, iron, copper, aluminium, cadmium, lead, mercury, arsenic, calcium, manganese, chromium, nickel, and phosphorus. The association between metallomic studies and psychiatry has been developing dynamically recently. According to the results of current research, metallomics might act as a potential screening tool for patients with MDD while at the same time providing an assessment of the severity of symptoms. Either deficiencies or excessive amounts of chosen elements might be associated with the progression of depressive symptoms or even the onset of the disease among people predisposed to MDD. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Neurological and Psychiatric Disease: A Decade of Progress)

Other

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12 pages, 488 KiB  
Perspective
Trans- and Cis-Phosphorylated Tau Protein: New Pieces of the Puzzle in the Development of Neurofibrillary Tangles in Post-Ischemic Brain Neurodegeneration of the Alzheimer’s Disease-like Type
by Ryszard Pluta and Stanisław J. Czuczwar
Int. J. Mol. Sci. 2024, 25(6), 3091; https://doi.org/10.3390/ijms25063091 - 7 Mar 2024
Cited by 5 | Viewed by 1868
Abstract
Recent evidence indicates that experimental brain ischemia leads to dementia with an Alzheimer’s disease-like type phenotype and genotype. Based on the above evidence, it was hypothesized that brain ischemia may contribute to the development of Alzheimer’s disease. Brain ischemia and Alzheimer’s disease are [...] Read more.
Recent evidence indicates that experimental brain ischemia leads to dementia with an Alzheimer’s disease-like type phenotype and genotype. Based on the above evidence, it was hypothesized that brain ischemia may contribute to the development of Alzheimer’s disease. Brain ischemia and Alzheimer’s disease are two diseases characterized by similar changes in the hippocampus that are closely related to memory impairment. Following brain ischemia in animals and humans, the presence of amyloid plaques in the extracellular space and intracellular neurofibrillary tangles was revealed. The phenomenon of tau protein hyperphosphorylation is a similar pathological feature of both post-ischemic brain injury and Alzheimer’s disease. In Alzheimer’s disease, the phosphorylated Thr231 motif in tau protein has two distinct trans and cis conformations and is the primary site of tau protein phosphorylation in the pre-entanglement cascade and acts as an early precursor of tau protein neuropathology in the form of neurofibrillary tangles. Based on the latest publication, we present a similar mechanism of the formation of neurofibrillary tangles after brain ischemia as in Alzheimer’s disease, established on trans- and cis-phosphorylation of tau protein, which ultimately influences the development of tauopathy. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Neurological and Psychiatric Disease: A Decade of Progress)
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