International Journal of Molecular Sciences

Review

23 pages, 1764 KiB

Open AccessReview

Advances and Challenges in Gene Therapy for Neurodegenerative Diseases: A Systematic Review

by Nerea García-González, Jaime Gonçalves-Sánchez, Ricardo Gómez-Nieto, Jesús M. Gonçalves-Estella and Dolores E. López

Int. J. Mol. Sci. 2024, 25(23), 12485; https://doi.org/10.3390/ijms252312485 - 21 Nov 2024

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Abstract

This review explores recent advancements in gene therapy as a potential treatment for neurodegenerative diseases, focusing on intervention mechanisms, administration routes, and associated limitations. Following the PRISMA procedure guidelines, we systematically analyzed studies published since 2020 using the PICO framework to derive reliable [...] Read more.

This review explores recent advancements in gene therapy as a potential treatment for neurodegenerative diseases, focusing on intervention mechanisms, administration routes, and associated limitations. Following the PRISMA procedure guidelines, we systematically analyzed studies published since 2020 using the PICO framework to derive reliable conclusions. The efficacy of various gene therapies was evaluated for Parkinson’s disease (n = 12), spinal muscular atrophy (n = 8), Huntington’s disease (n = 3), Alzheimer’s disease (n = 3), and amyotrophic lateral sclerosis (n = 6). For each condition, we assessed the therapeutic approach, curative or disease-modifying potential, delivery methods, advantages, drawbacks, and side effects. Results indicate that gene therapies targeting specific genes are particularly effective in monogenic disorders, with promising clinical outcomes expected in the near future. In contrast, in polygenic diseases, therapies primarily aim to promote cell survival. A major challenge remains: the translation of animal model success to human clinical application. Additionally, while intracerebral delivery methods enhance therapeutic efficacy, they are highly invasive. Despite these hurdles, gene therapy represents a promising frontier in the treatment of neurodegenerative diseases, underscoring the need for continued research to refine and personalize treatments for each condition. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Neurobiology 2024)

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33 pages, 918 KiB

Open AccessReview

The Role of Oxytocin and Vasopressin in People with Borderline Personality Disorder: A Closer Look at Adolescents

by Magdalena Uzar, Monika Dmitrzak-Węglarz and Agnieszka Słopień

Int. J. Mol. Sci. 2024, 25(22), 12046; https://doi.org/10.3390/ijms252212046 - 9 Nov 2024

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Abstract

Borderline personality disorder constitutes a significant medical challenge. Despite the fact that its occurrence among adolescents is currently attracting increasing interest from both clinicians and researchers, there is still insufficient data on this phenomenon. The etiology and maintenance of borderline personality disorder are [...] Read more.

Borderline personality disorder constitutes a significant medical challenge. Despite the fact that its occurrence among adolescents is currently attracting increasing interest from both clinicians and researchers, there is still insufficient data on this phenomenon. The etiology and maintenance of borderline personality disorder are not yet fully comprehended. Neuropeptides, including oxytocin and vasopressin, are considered to be involved in the development of this condition. The mechanism behind the actions of these neurohormones requires further investigation. Our work aims to collect and analyze the available research and existing hypotheses on the role of oxytocin and vasopressin in people with borderline personality disorder, with special attention drawn to adolescents suffering from this condition. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Neurobiology 2024)

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49 pages, 2110 KiB

Open AccessReview

Reviewing the Structure–Function Paradigm in Polyglutamine Disorders: A Synergistic Perspective on Theoretical and Experimental Approaches

by Nastasia Sanda Moldovean-Cioroianu

Int. J. Mol. Sci. 2024, 25(12), 6789; https://doi.org/10.3390/ijms25126789 - 20 Jun 2024

Viewed by 1151

Abstract

Polyglutamine (polyQ) disorders are a group of neurodegenerative diseases characterized by the excessive expansion of CAG (cytosine, adenine, guanine) repeats within host proteins. The quest to unravel the complex diseases mechanism has led researchers to adopt both theoretical and experimental methods, each offering [...] Read more.

Polyglutamine (polyQ) disorders are a group of neurodegenerative diseases characterized by the excessive expansion of CAG (cytosine, adenine, guanine) repeats within host proteins. The quest to unravel the complex diseases mechanism has led researchers to adopt both theoretical and experimental methods, each offering unique insights into the underlying pathogenesis. This review emphasizes the significance of combining multiple approaches in the study of polyQ disorders, focusing on the structure–function correlations and the relevance of polyQ-related protein dynamics in neurodegeneration. By integrating computational/theoretical predictions with experimental observations, one can establish robust structure–function correlations, aiding in the identification of key molecular targets for therapeutic interventions. PolyQ proteins’ dynamics, influenced by their length and interactions with other molecular partners, play a pivotal role in the polyQ-related pathogenic cascade. Moreover, conformational dynamics of polyQ proteins can trigger aggregation, leading to toxic assembles that hinder proper cellular homeostasis. Understanding these intricacies offers new avenues for therapeutic strategies by fine-tuning polyQ kinetics, in order to prevent and control disease progression. Last but not least, this review highlights the importance of integrating multidisciplinary efforts to advancing research in this field, bringing us closer to the ultimate goal of finding effective treatments against polyQ disorders. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Neurobiology 2024)

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17 pages, 439 KiB

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Emerging Therapeutic Potential of Fluoxetine on Cognitive Decline in Alzheimer’s Disease: Systematic Review

by Anastasia Bougea, Efthalia Angelopoulou, Efthimios Vasilopoulos, Philippos Gourzis and Sokratis Papageorgiou

Int. J. Mol. Sci. 2024, 25(12), 6542; https://doi.org/10.3390/ijms25126542 - 13 Jun 2024

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Abstract

Fluoxetine, a commonly prescribed medication for depression, has been studied in Alzheimer’s disease (AD) patients for its effectiveness on cognitive symptoms. The aim of this systematic review is to investigate the therapeutic potential of fluoxetine in cognitive decline in AD, focusing on its [...] Read more.

Fluoxetine, a commonly prescribed medication for depression, has been studied in Alzheimer’s disease (AD) patients for its effectiveness on cognitive symptoms. The aim of this systematic review is to investigate the therapeutic potential of fluoxetine in cognitive decline in AD, focusing on its anti-degenerative mechanisms of action and clinical implications. According to PRISMA, we searched MEDLINE, up to 1 April 2024, for animal and human studies examining the efficacy of fluoxetine with regard to the recovery of cognitive function in AD. Methodological quality was evaluated using the ARRIVE tool for animal AD studies and the Cochrane tool for clinical trials. In total, 22 studies were analyzed (19 animal AD studies and 3 clinical studies). Fluoxetine promoted neurogenesis and enhanced synaptic plasticity in preclinical models of AD, through a decrease in Aβ pathology and increase in BDNF, by activating diverse pathways (such as the DAF-16-mediated, TGF-beta1, ILK-AKT-GSK3beta, and CREB/p-CREB/BDNF). In addition, fluoxetine has anti-inflammatory properties/antioxidant effects via targeting antioxidant Nrf2/HO-1 and hindering TLR4/NLRP3 inflammasome. Only three clinical studies showed that fluoxetine ameliorated the cognitive performance of people with AD; however, several methodological issues limited the generalizability of these results. Overall, the high-quality preclinical evidence suggests that fluoxetine may have neuroprotective, antioxidant, and anti-inflammatory effects in AD animal models. While more high-quality clinical research is needed to fully understand the mechanisms underlying these effects, fluoxetine is a promising potential treatment for AD patients. If future clinical trials confirm its anti-degenerative and neuroprotective effects, fluoxetine could offer a new therapeutic approach for slowing down the progression of AD. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Neurobiology 2024)

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23 pages, 2217 KiB

Open AccessReview

Valosin-Containing Protein (VCP): A Review of Its Diverse Molecular Functions and Clinical Phenotypes

by Carly S. Pontifex, Mashiat Zaman, Roberto D. Fanganiello, Timothy E. Shutt and Gerald Pfeffer

Int. J. Mol. Sci. 2024, 25(11), 5633; https://doi.org/10.3390/ijms25115633 - 22 May 2024

Cited by 1 | Viewed by 1964

Abstract

In this review we examine the functionally diverse ATPase associated with various cellular activities (AAA-ATPase), valosin-containing protein (VCP/p97), its molecular functions, the mutational landscape of VCP and the phenotypic manifestation of VCP disease. VCP is crucial to a multitude of cellular functions including [...] Read more.

In this review we examine the functionally diverse ATPase associated with various cellular activities (AAA-ATPase), valosin-containing protein (VCP/p97), its molecular functions, the mutational landscape of VCP and the phenotypic manifestation of VCP disease. VCP is crucial to a multitude of cellular functions including protein quality control, endoplasmic reticulum-associated degradation (ERAD), autophagy, mitophagy, lysophagy, stress granule formation and clearance, DNA replication and mitosis, DNA damage response including nucleotide excision repair, ATM- and ATR-mediated damage response, homologous repair and non-homologous end joining. VCP variants cause multisystem proteinopathy, and pathology can arise in several tissue types such as skeletal muscle, bone, brain, motor neurons, sensory neurons and possibly cardiac muscle, with the disease course being challenging to predict. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Neurobiology 2024)

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18 pages, 394 KiB

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Parvalbumin Interneuron Dysfunction in Neurological Disorders: Focus on Epilepsy and Alzheimer’s Disease

by Beulah Leitch

Int. J. Mol. Sci. 2024, 25(10), 5549; https://doi.org/10.3390/ijms25105549 - 19 May 2024

Cited by 3 | Viewed by 2616

Abstract

Parvalbumin expressing (PV+) GABAergic interneurons are fast spiking neurons that provide powerful but relatively short-lived inhibition to principal excitatory cells in the brain. They play a vital role in feedforward and feedback synaptic inhibition, preventing run away excitation in neural networks. Hence, their [...] Read more.

Parvalbumin expressing (PV+) GABAergic interneurons are fast spiking neurons that provide powerful but relatively short-lived inhibition to principal excitatory cells in the brain. They play a vital role in feedforward and feedback synaptic inhibition, preventing run away excitation in neural networks. Hence, their dysfunction can lead to hyperexcitability and increased susceptibility to seizures. PV+ interneurons are also key players in generating gamma oscillations, which are synchronized neural oscillations associated with various cognitive functions. PV+ interneuron are particularly vulnerable to aging and their degeneration has been associated with cognitive decline and memory impairment in dementia and Alzheimer’s disease (AD). Overall, dysfunction of PV+ interneurons disrupts the normal excitatory/inhibitory balance within specific neurocircuits in the brain and thus has been linked to a wide range of neurodevelopmental and neuropsychiatric disorders. This review focuses on the role of dysfunctional PV+ inhibitory interneurons in the generation of epileptic seizures and cognitive impairment and their potential as targets in the design of future therapeutic strategies to treat these disorders. Recent research using cutting-edge optogenetic and chemogenetic technologies has demonstrated that they can be selectively manipulated to control seizures and restore the balance of neural activity in the brains of animal models. This suggests that PV+ interneurons could be important targets in developing future treatments for patients with epilepsy and comorbid disorders, such as AD, where seizures and cognitive decline are directly linked to specific PV+ interneuron deficits. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Neurobiology 2024)

15 pages, 8264 KiB

Open AccessReview

Molecular, Morphological and Electrophysiological Differences between Alpha and Gamma Motoneurons with Special Reference to the Trigeminal Motor Nucleus of Rat

by Youngnam Kang, Mitsuru Saito and Hiroki Toyoda

Int. J. Mol. Sci. 2024, 25(10), 5266; https://doi.org/10.3390/ijms25105266 - 12 May 2024

Cited by 1 | Viewed by 1015

Abstract

The muscle contraction during voluntary movement is controlled by activities of alpha- and gamma-motoneurons (αMNs and γMNs, respectively). In spite of the recent advances in research on molecular markers that can distinguish between αMNs and γMNs, electrophysiological membrane properties and firing patterns of [...] Read more.

The muscle contraction during voluntary movement is controlled by activities of alpha- and gamma-motoneurons (αMNs and γMNs, respectively). In spite of the recent advances in research on molecular markers that can distinguish between αMNs and γMNs, electrophysiological membrane properties and firing patterns of γMNs have remained unknown, while those of αMNs have been clarified in detail. Because of the larger size of αMNs compared to γMNs, blindly or even visually recorded MNs were mostly αMNs, as demonstrated with molecular markers recently. Subsequently, the research on αMNs has made great progress in classifying their subtypes based on the molecular markers and electrophysiological membrane properties, whereas only a few studies demonstrated the electrophysiological membrane properties of γMNs. In this review article, we provide an overview of the recent advances in research on the classification of αMNs and γMNs based on molecular markers and electrophysiological membrane properties, and discuss their functional implication and significance in motor control. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Neurobiology 2024)

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16 pages, 600 KiB

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Epigenetics, Nutrition, and the Brain: Improving Mental Health through Diet

by Rola A. Bekdash

Int. J. Mol. Sci. 2024, 25(7), 4036; https://doi.org/10.3390/ijms25074036 - 4 Apr 2024

Cited by 3 | Viewed by 8791

Abstract

The relationship between nutrition and brain health is intricate. Studies suggest that nutrients during early life impact not only human physiology but also mental health. Although the exact molecular mechanisms that depict this relationship remain unclear, there are indications that environmental factors such [...] Read more.

The relationship between nutrition and brain health is intricate. Studies suggest that nutrients during early life impact not only human physiology but also mental health. Although the exact molecular mechanisms that depict this relationship remain unclear, there are indications that environmental factors such as eating, lifestyle habits, stress, and physical activity, influence our genes and modulate their function by epigenetic mechanisms to shape mental health outcomes. Epigenetic mechanisms act as crucial link between genes and environmental influences, proving that non-genetic factors could have enduring effects on the epigenome and influence health trajectories. We review studies that demonstrated an epigenetic mechanism of action of nutrition on mental health, focusing on the role of specific micronutrients during critical stages of brain development. The methyl-donor micronutrients of the one-carbon metabolism, such as choline, betaine, methionine, folic acid, VitB6 and VitB12 play critical roles in various physiological processes, including DNA and histone methylation. These micronutrients have been shown to alter gene function and susceptibility to diseases including mental health and metabolic disorders. Understanding how micronutrients influence metabolic genes in humans can lead to the implementation of early nutritional interventions to reduce the risk of developing metabolic and mental health disorders later in life. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Neurobiology 2024)

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20 pages, 3544 KiB

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Kynurenines, Neuronal Excitotoxicity, and Mitochondrial Oxidative Stress: Role of the Intestinal Flora

by Gábor Nagy-Grócz, Eleonóra Spekker and László Vécsei

Int. J. Mol. Sci. 2024, 25(3), 1698; https://doi.org/10.3390/ijms25031698 - 30 Jan 2024

Cited by 7 | Viewed by 2322

Abstract

The intestinal flora has been the focus of numerous investigations recently, with inquiries not just into the gastrointestinal aspects but also the pathomechanism of other diseases such as nervous system disorders and mitochondrial diseases. Mitochondrial disorders are the most common type of inheritable [...] Read more.

The intestinal flora has been the focus of numerous investigations recently, with inquiries not just into the gastrointestinal aspects but also the pathomechanism of other diseases such as nervous system disorders and mitochondrial diseases. Mitochondrial disorders are the most common type of inheritable metabolic illness caused by mutations of mitochondrial and nuclear DNA. Despite the intensive research, its diagnosis is usually difficult, and unfortunately, treating it challenges physicians. Metabolites of the kynurenine pathway are linked to many disorders, such as depression, schizophrenia, migraine, and also diseases associated with impaired mitochondrial function. The kynurenine pathway includes many substances, for instance kynurenic acid and quinolinic acid. In this review, we would like to show a possible link between the metabolites of the kynurenine pathway and mitochondrial stress in the context of intestinal flora. Furthermore, we summarize the possible markers of and future therapeutic options for the kynurenine pathway in excitotoxicity and mitochondrial oxidative stress. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Neurobiology 2024)

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