International Journal of Molecular Sciences

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38 pages, 3597 KiB

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Spinal Muscular Atrophy: The Past, Present, and Future of Diagnosis and Treatment

by Hisahide Nishio, Emma Tabe Eko Niba, Toshio Saito, Kentaro Okamoto, Yasuhiro Takeshima and Hiroyuki Awano

Int. J. Mol. Sci. 2023, 24(15), 11939; https://doi.org/10.3390/ijms241511939 - 26 Jul 2023

Cited by 55 | Viewed by 17320

Abstract

Spinal muscular atrophy (SMA) is a lower motor neuron disease with autosomal recessive inheritance. The first cases of SMA were reported by Werdnig in 1891. Although the phenotypic variation of SMA led to controversy regarding the clinical entity of the disease, the genetic [...] Read more.

Spinal muscular atrophy (SMA) is a lower motor neuron disease with autosomal recessive inheritance. The first cases of SMA were reported by Werdnig in 1891. Although the phenotypic variation of SMA led to controversy regarding the clinical entity of the disease, the genetic homogeneity of SMA was proved in 1990. Five years later, in 1995, the gene responsible for SMA, SMN1, was identified. Genetic testing of SMN1 has enabled precise epidemiological studies, revealing that SMA occurs in 1 of 10,000 to 20,000 live births and that more than 95% of affected patients are homozygous for SMN1 deletion. In 2016, nusinersen was the first drug approved for treatment of SMA in the United States. Two other drugs were subsequently approved: onasemnogene abeparvovec and risdiplam. Clinical trials with these drugs targeting patients with pre-symptomatic SMA (those who were diagnosed by genetic testing but showed no symptoms) revealed that such patients could achieve the milestones of independent sitting and/or walking. Following the great success of these trials, population-based newborn screening programs for SMA (more precisely, SMN1-deleted SMA) have been increasingly implemented worldwide. Early detection by newborn screening and early treatment with new drugs are expected to soon become the standards in the field of SMA. Full article

(This article belongs to the Special Issue Latest Review Papers in Neurobiology 2023)

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13 pages, 827 KiB

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Fc Epsilon RI–Neuroimmune Interplay in Pruritus Triggered by Particulate Matter in Atopic Dermatitis Patients

by Dina Isaifan, Sergio Crovella, Lama Soubra, Maryam Al-Nesf and Martin Steinhoff

Int. J. Mol. Sci. 2023, 24(14), 11851; https://doi.org/10.3390/ijms241411851 - 24 Jul 2023

Cited by 2 | Viewed by 2078

Abstract

Atopic dermatitis (AD) is the most common chronic relapsing neuroinflammatory skin disease that is characterized by a complex and multifactorial pathophysiology. It reflects a profound interplay between genetic and environmental factors, and a recently disclosed neuroimmune dysregulation that drives skin barrier disruption, pruritus, [...] Read more.

Atopic dermatitis (AD) is the most common chronic relapsing neuroinflammatory skin disease that is characterized by a complex and multifactorial pathophysiology. It reflects a profound interplay between genetic and environmental factors, and a recently disclosed neuroimmune dysregulation that drives skin barrier disruption, pruritus, and microbial imbalance. In terms of the key external environmental players that impact AD, air quality and itch severity linkage have been thoroughly researched. The impact of ambient air pollutants including particulate matter (PM) and AD pruritic exacerbation has been recorded despite reductions in air pollution levels in in developed countries. The developing countries have, on the contrary, experienced significant urbanization and industrialization with limited environmental protection standards in the past decades. This unprecedented construction, petrochemical industry utilization, and increment in population counts has been paired with consistent exposure to outdoor PM. This may present a key cause of AD pruritic exacerbation supported by the fact that AD prevalence has intensified globally in the past 50 years, indicating that environmental exposure may act as a trigger that could flare up itch in vulnerable persons. At the molecular level, the impact of PM on severe pruritus in AD could be interpreted by the toxic effects on the complex neuroimmune pathways that govern this disease. AD has been recently viewed as a manifestation of the disruption of both the immune and neurological systems. In light of these facts, this current review aims to introduce the basic concepts of itch sensory circuits in the neuroimmune system. In addition, it describes the impact of PM on the potential neuroimmune pathways in AD pathogenesis with a special focus on the Fc Epsilon RI pathway. Finally, the review proposes potential treatment lines that could be targeted to alleviate pruritus based on immune mediators involved in the Fc Epsilon signaling map. Full article

(This article belongs to the Special Issue Latest Review Papers in Neurobiology 2023)

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17 pages, 623 KiB

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ACSL4-Mediated Ferroptosis and Its Potential Role in Central Nervous System Diseases and Injuries

by Bowen Jia, Jing Li, Yiting Song and Chengliang Luo

Int. J. Mol. Sci. 2023, 24(12), 10021; https://doi.org/10.3390/ijms241210021 - 12 Jun 2023

Cited by 43 | Viewed by 6865

Abstract

As an iron-dependent regulated form of cell death, ferroptosis is characterized by iron-dependent lipid peroxidation and has been implicated in the occurrence and development of various diseases, including nervous system diseases and injuries. Ferroptosis has become a potential target for intervention in these [...] Read more.

As an iron-dependent regulated form of cell death, ferroptosis is characterized by iron-dependent lipid peroxidation and has been implicated in the occurrence and development of various diseases, including nervous system diseases and injuries. Ferroptosis has become a potential target for intervention in these diseases or injuries in relevant preclinical models. As a member of the Acyl-CoA synthetase long-chain family (ACSLs) that can convert saturated and unsaturated fatty acids, Acyl—CoA synthetase long-chain familymember4 (ACSL4) is involved in the regulation of arachidonic acid and eicosapentaenoic acid, thus leading to ferroptosis. The underlying molecular mechanisms of ACSL4-mediated ferroptosis will promote additional treatment strategies for these diseases or injury conditions. Our review article provides a current view of ACSL4-mediated ferroptosis, mainly including the structure and function of ACSL4, as well as the role of ACSL4 in ferroptosis. We also summarize the latest research progress of ACSL4-mediated ferroptosis in central nervous system injuries and diseases, further proving that ACSL4-medicated ferroptosis is an important target for intervention in these diseases or injuries. Full article

(This article belongs to the Special Issue Latest Review Papers in Neurobiology 2023)

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13 pages, 1036 KiB

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SOX2-Sensing: Insights into the Role of SOX2 in the Generation of Sensory Cell Types in Vertebrates

by Sara Mercurio

Int. J. Mol. Sci. 2023, 24(8), 7637; https://doi.org/10.3390/ijms24087637 - 21 Apr 2023

Viewed by 2563

Abstract

The SOX2 transcription factor is a key regulator of nervous system development, and its mutation in humans leads to a rare disease characterized by severe eye defects, cognitive defects, hearing defects, abnormalities of the CNS and motor control problems. SOX2 has an essential [...] Read more.

The SOX2 transcription factor is a key regulator of nervous system development, and its mutation in humans leads to a rare disease characterized by severe eye defects, cognitive defects, hearing defects, abnormalities of the CNS and motor control problems. SOX2 has an essential role in neural stem cell maintenance in specific regions of the brain, and it is one of the master genes required for the generation of induced pluripotent stem cells. Sox2 is expressed in sensory organs, and this review will illustrate how it regulates the differentiation of sensory cell types required for hearing, touching, tasting and smelling in vertebrates and, in particular, in mice. Full article

(This article belongs to the Special Issue Latest Review Papers in Neurobiology 2023)

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18 pages, 1499 KiB

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A Review of Research on the Association between Neuron–Astrocyte Signaling Processes and Depressive Symptoms

by Jiao Yao, Cong Chen, Yi Guo, Yantao Yang, Xinya Liu, Shifeng Chu, Qidi Ai, Zhao Zhang, Meiyu Lin, Songwei Yang and Naihong Chen

Int. J. Mol. Sci. 2023, 24(8), 6985; https://doi.org/10.3390/ijms24086985 - 10 Apr 2023

Cited by 10 | Viewed by 3938

Abstract

Depression is a mental illness that has a serious negative impact on physical and mental health. The pathophysiology of depression is still unknown, and therapeutic medications have drawbacks, such as poor effectiveness, strong dependence, adverse drug withdrawal symptoms, and harmful side effects. Therefore, [...] Read more.

Depression is a mental illness that has a serious negative impact on physical and mental health. The pathophysiology of depression is still unknown, and therapeutic medications have drawbacks, such as poor effectiveness, strong dependence, adverse drug withdrawal symptoms, and harmful side effects. Therefore, the primary purpose of contemporary research is to understand the exact pathophysiology of depression. The connection between astrocytes, neurons, and their interactions with depression has recently become the focus of great research interest. This review summarizes the pathological changes of neurons and astrocytes, and their interactions in depression, including the alterations of mid-spiny neurons and pyramidal neurons, the alterations of astrocyte-related biomarkers, and the alterations of gliotransmitters between astrocytes and neurons. In addition to providing the subjects of this research and suggestions for the pathogenesis and treatment techniques of depression, the intention of this article is to more clearly identify links between neuronal–astrocyte signaling processes and depressive symptoms. Full article

(This article belongs to the Special Issue Latest Review Papers in Neurobiology 2023)

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14 pages, 1424 KiB

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Macrophage–Neuroglia Interactions in Promoting Neuronal Regeneration in Zebrafish

by Chih-Wei Zeng

Int. J. Mol. Sci. 2023, 24(7), 6483; https://doi.org/10.3390/ijms24076483 - 30 Mar 2023

Cited by 13 | Viewed by 3663

Abstract

The human nervous system exhibits limited regenerative capabilities following damage to the central nervous system (CNS), leading to a scarcity of effective treatments for nerve function recovery. In contrast, zebrafish demonstrate remarkable regenerative abilities, making them an ideal model for studying the modulation [...] Read more.

The human nervous system exhibits limited regenerative capabilities following damage to the central nervous system (CNS), leading to a scarcity of effective treatments for nerve function recovery. In contrast, zebrafish demonstrate remarkable regenerative abilities, making them an ideal model for studying the modulation of inflammatory processes after injury. Such research holds significant translational potential to enhance our understanding of recovery from damage and disease. Macrophages play a crucial role in tissue repair and regeneration, with their subpopulations indirectly promoting axonal regeneration through developmental signals. The AP-1 signaling pathway, mediated by TNF/Tnfrsf1a, can elevate HDAC1 expression and facilitate regeneration. Furthermore, following spinal cord injury (SCI), pMN progenitors have been observed to switch between oligodendrocyte and motor neuron fates, with macrophage-secreted TNF-α potentially regulating the differentiation of ependymal–radial glia progenitors and oligodendrocytes. Radial glial cells (RGs) are also essential for CNS regeneration in zebrafish, as they perform neurogenesis and gliogenesis, with specific RG subpopulations potentially existing for the generation of neurons and oligodendrocytes. This review article underscores the critical role of macrophages and their subpopulations in tissue repair and regeneration, focusing on their secretion of TNF-α, which promotes axonal regeneration in zebrafish. We also offer insights into the molecular mechanisms underlying TNF-α’s ability to facilitate axonal regeneration and explore the potential of pMN progenitor cells and RGs following SCI in zebrafish. The review concludes with a discussion of various unresolved questions in the field, and ideas are suggested for future research. Studying innate immune cell interactions with neuroglia following injury may lead to the development of novel strategies for treating the inflammatory processes associated with regenerative medicine, which are commonly observed in injury and disease. Full article

(This article belongs to the Special Issue Latest Review Papers in Neurobiology 2023)

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22 pages, 1238 KiB

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Dopamine Transmission Imbalance in Neuroinflammation: Perspectives on Long-Term COVID-19

by Maria Mancini, Silvia Natoli, Fabrizio Gardoni, Monica Di Luca and Antonio Pisani

Int. J. Mol. Sci. 2023, 24(6), 5618; https://doi.org/10.3390/ijms24065618 - 15 Mar 2023

Cited by 12 | Viewed by 11252

Abstract

Dopamine (DA) is a key neurotransmitter in the basal ganglia, implicated in the control of movement and motivation. Alteration of DA levels is central in Parkinson’s disease (PD), a common neurodegenerative disorder characterized by motor and non-motor manifestations and deposition of alpha-synuclein (α-syn) [...] Read more.

Dopamine (DA) is a key neurotransmitter in the basal ganglia, implicated in the control of movement and motivation. Alteration of DA levels is central in Parkinson’s disease (PD), a common neurodegenerative disorder characterized by motor and non-motor manifestations and deposition of alpha-synuclein (α-syn) aggregates. Previous studies have hypothesized a link between PD and viral infections. Indeed, different cases of parkinsonism have been reported following COVID-19. However, whether SARS-CoV-2 may trigger a neurodegenerative process is still a matter of debate. Interestingly, evidence of brain inflammation has been described in postmortem samples of patients infected by SARS-CoV-2, which suggests immune-mediated mechanisms triggering the neurological sequelae. In this review, we discuss the role of proinflammatory molecules such as cytokines, chemokines, and oxygen reactive species in modulating DA homeostasis. Moreover, we review the existing literature on the possible mechanistic interplay between SARS-CoV-2-mediated neuroinflammation and nigrostriatal DAergic impairment, and the cross-talk with aberrant α-syn metabolism. Full article

(This article belongs to the Special Issue Latest Review Papers in Neurobiology 2023)

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40 pages, 1867 KiB

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Status of Metabolomic Measurement for Insights in Alzheimer’s Disease Progression—What Is Missing?

by Chunyuan Yin, Amy C. Harms, Thomas Hankemeier, Alida Kindt and Elizabeth C. M. de Lange

Int. J. Mol. Sci. 2023, 24(5), 4960; https://doi.org/10.3390/ijms24054960 - 4 Mar 2023

Cited by 12 | Viewed by 3931

Abstract

Alzheimer’s disease (AD) is an aging-related neurodegenerative disease, leading to the progressive loss of memory and other cognitive functions. As there is still no cure for AD, the growth in the number of susceptible individuals represents a major emerging threat to public health. [...] Read more.

Alzheimer’s disease (AD) is an aging-related neurodegenerative disease, leading to the progressive loss of memory and other cognitive functions. As there is still no cure for AD, the growth in the number of susceptible individuals represents a major emerging threat to public health. Currently, the pathogenesis and etiology of AD remain poorly understood, while no efficient treatments are available to slow down the degenerative effects of AD. Metabolomics allows the study of biochemical alterations in pathological processes which may be involved in AD progression and to discover new therapeutic targets. In this review, we summarized and analyzed the results from studies on metabolomics analysis performed in biological samples of AD subjects and AD animal models. Then this information was analyzed by using MetaboAnalyst to find the disturbed pathways among different sample types in human and animal models at different disease stages. We discuss the underlying biochemical mechanisms involved, and the extent to which they could impact the specific hallmarks of AD. Then we identify gaps and challenges and provide recommendations for future metabolomics approaches to better understand AD pathogenesis. Full article

(This article belongs to the Special Issue Latest Review Papers in Neurobiology 2023)

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18 pages, 1965 KiB

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Recent Insights into the Functional Role of AMPA Receptors in the Oligodendrocyte Lineage Cells In Vivo

by Maria Kukley

Int. J. Mol. Sci. 2023, 24(4), 4138; https://doi.org/10.3390/ijms24044138 - 18 Feb 2023

Cited by 5 | Viewed by 2257

Abstract

This review discusses the experimental findings of several recent studies which investigated the functional role of AMPA receptors (AMPARs) in oligodendrocyte lineage cells in vivo, in mice and in zebrafish. These studies provided valuable information showing that oligodendroglial AMPARs may be involved in [...] Read more.

This review discusses the experimental findings of several recent studies which investigated the functional role of AMPA receptors (AMPARs) in oligodendrocyte lineage cells in vivo, in mice and in zebrafish. These studies provided valuable information showing that oligodendroglial AMPARs may be involved in the modulation of proliferation, differentiation, and migration of oligodendroglial progenitors, as well as survival of myelinating oligodendrocytes during physiological conditions in vivo. They also suggested that targeting the subunit composition of AMPARs may be an important strategy for treating diseases. However, at the same time, the experimental findings taken together still do not provide a clear picture on the topic. Hence, new ideas and new experimental designs are required for understanding the functional role of AMPARs in the oligodendrocyte lineage cells in vivo. It is also necessary to consider more closely the temporal and spatial aspects of AMPAR-mediated signalling in the oligodendrocyte lineage cells. These two important aspects are routinely discussed by neuronal physiologists studying glutamatergic synaptic transmission, but are rarely debated and thought about by researchers studying glial cells. Full article

(This article belongs to the Special Issue Latest Review Papers in Neurobiology 2023)

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12 pages, 606 KiB

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P188 Therapy in In Vitro Models of Traumatic Brain Injury

by Michael Zargari, Luise J. Meyer, Matthias L. Riess, Zhu Li and Matthew B. Barajas

Int. J. Mol. Sci. 2023, 24(4), 3334; https://doi.org/10.3390/ijms24043334 - 7 Feb 2023

Cited by 6 | Viewed by 2786

Abstract

Traumatic brain injury (TBI) is a significant cause of morbidity and mortality worldwide. Varied mechanisms of injury contribute to the heterogeneity of this patient population as demonstrated by the multiple published grading scales and diverse required criteria leading to diagnoses from mild to [...] Read more.

Traumatic brain injury (TBI) is a significant cause of morbidity and mortality worldwide. Varied mechanisms of injury contribute to the heterogeneity of this patient population as demonstrated by the multiple published grading scales and diverse required criteria leading to diagnoses from mild to severe. TBI pathophysiology is classically separated into a primary injury that is characterized by local tissue destruction as a result of the initial blow, followed by a secondary phase of injury constituted by a score of incompletely understood cellular processes including reperfusion injury, disruption to the blood-brain barrier, excitotoxicity, and metabolic dysregulation. There are currently no effective pharmacological treatments in the wide-spread use for TBI, in large part due to challenges associated with the development of clinically representative in vitro and in vivo models. Poloxamer 188 (P188), a Food and Drug Administration-approved amphiphilic triblock copolymer embeds itself into the plasma membrane of damaged cells. P188 has been shown to have neuroprotective properties on various cell types. The objective of this review is to provide a summary of the current literature on in vitro models of TBI treated with P188. Full article

(This article belongs to the Special Issue Latest Review Papers in Neurobiology 2023)

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23 pages, 3242 KiB

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Review of Technological Challenges in Personalised Medicine and Early Diagnosis of Neurodegenerative Disorders

by Celtia Domínguez-Fernández, June Egiguren-Ortiz, Jone Razquin, Margarita Gómez-Galán, Laura De las Heras-García, Elena Paredes-Rodríguez, Egoitz Astigarraga, Cristina Miguélez and Gabriel Barreda-Gómez

Int. J. Mol. Sci. 2023, 24(4), 3321; https://doi.org/10.3390/ijms24043321 - 7 Feb 2023

Cited by 23 | Viewed by 4775

Abstract

Neurodegenerative disorders are characterised by progressive neuron loss in specific brain areas. The most common are Alzheimer’s disease and Parkinson’s disease; in both cases, diagnosis is based on clinical tests with limited capability to discriminate between similar neurodegenerative disorders and detect the early [...] Read more.

Neurodegenerative disorders are characterised by progressive neuron loss in specific brain areas. The most common are Alzheimer’s disease and Parkinson’s disease; in both cases, diagnosis is based on clinical tests with limited capability to discriminate between similar neurodegenerative disorders and detect the early stages of the disease. It is common that by the time a patient is diagnosed with the disease, the level of neurodegeneration is already severe. Thus, it is critical to find new diagnostic methods that allow earlier and more accurate disease detection. This study reviews the methods available for the clinical diagnosis of neurodegenerative diseases and potentially interesting new technologies. Neuroimaging techniques are the most widely used in clinical practice, and new techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET) have significantly improved the diagnosis quality. Identifying biomarkers in peripheral samples such as blood or cerebrospinal fluid is a major focus of the current research on neurodegenerative diseases. The discovery of good markers could allow preventive screening to identify early or asymptomatic stages of the neurodegenerative process. These methods, in combination with artificial intelligence, could contribute to the generation of predictive models that will help clinicians in the early diagnosis, stratification, and prognostic assessment of patients, leading to improvements in patient treatment and quality of life. Full article

(This article belongs to the Special Issue Latest Review Papers in Neurobiology 2023)

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23 pages, 2818 KiB

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Circulating MicroRNAs and Extracellular Vesicle-Derived MicroRNAs as Predictors of Functional Recovery in Ischemic Stroke Patients: A Systematic Review and Meta-Analysis

by Codrin-Constantin Burlacu, Daniela Ciobanu, Andrei-Vlad Badulescu, Vlad-Florin Chelaru, Andrei-Otto Mitre, Bogdan Capitanescu, Dirk M. Hermann and Aurel Popa-Wagner

Int. J. Mol. Sci. 2023, 24(1), 251; https://doi.org/10.3390/ijms24010251 - 23 Dec 2022

Cited by 14 | Viewed by 3678

Abstract

Stroke accounts for the second leading cause of death and a major cause of disability, with limited therapeutic strategy in both the acute and chronic phases. Blood-based biomarkers are intensively researched and widely recognized as useful tools to predict the prognoses of patients [...] Read more.

Stroke accounts for the second leading cause of death and a major cause of disability, with limited therapeutic strategy in both the acute and chronic phases. Blood-based biomarkers are intensively researched and widely recognized as useful tools to predict the prognoses of patients confronted with therapeutically limited diseases. We performed a systematic review of the circulating biomarkers in IS patients with prognostic value, with a focus on microRNAs and exosomes as predictive biomarkers of motor and cognitive recovery. We identified 63 studies, totalizing 72 circulating biomarkers with prognostic value in stroke recovery, as follows: 68 miRNAs and exosomal-miRNAs being identified as predictive for motor recovery after stroke, and seven biomarkers being predictive for cognitive recovery. Twelve meta-analyses were performed using effect sizes (random-effects and fixed-effects model). The most significant correlation findings obtained after pooling were with miR-21, miR-29b, miR-125b-5p, miR-126, and miR-335. We identified several miRNAs that were correlated with clinical outcomes of stroke severity and recovery after ischemic stroke, providing predictive information on motor and cognitive recovery. Based on the current state of research, we identified serum miR-9 and neutrophil miR-29b as the most promising biomarkers for in-depth follow-up studies, followed by serum miR-124 and plasma miR-125b. Full article

(This article belongs to the Special Issue Latest Review Papers in Neurobiology 2023)

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33 pages, 2534 KiB

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Microglia and Brain Macrophages as Drivers of Glioma Progression

by Yuqi Zheng and Manuel B. Graeber

Int. J. Mol. Sci. 2022, 23(24), 15612; https://doi.org/10.3390/ijms232415612 - 9 Dec 2022

Cited by 20 | Viewed by 6584

Abstract

Evidence is accumulating that the tumour microenvironment (TME) has a key role in the progression of gliomas. Non-neoplastic cells in addition to the tumour cells are therefore finding increasing attention. Microglia and other glioma-associated macrophages are at the centre of this interest especially [...] Read more.

Evidence is accumulating that the tumour microenvironment (TME) has a key role in the progression of gliomas. Non-neoplastic cells in addition to the tumour cells are therefore finding increasing attention. Microglia and other glioma-associated macrophages are at the centre of this interest especially in the context of therapeutic considerations. New ideas have emerged regarding the role of microglia and, more recently, blood-derived brain macrophages in glioblastoma (GBM) progression. We are now beginning to understand the mechanisms that allow malignant glioma cells to weaken microglia and brain macrophage defence mechanisms. Surface molecules and cytokines have a prominent role in microglia/macrophage-glioma cell interactions, and we discuss them in detail. The involvement of exosomes and microRNAs forms another focus of this review. In addition, certain microglia and glioma cell pathways deserve special attention. These “synergistic” (we suggest calling them “Janus”) pathways are active in both glioma cells and microglia/macrophages where they act in concert supporting malignant glioma progression. Examples include CCN4 (WISP1)/Integrin α6β1/Akt and CHI3L1/PI3K/Akt/mTOR. They represent attractive therapeutic targets. Full article

(This article belongs to the Special Issue Latest Review Papers in Neurobiology 2023)

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