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Viruses Oct 2021Over the years, viral infections have caused severe illness in humans. Zika Virus (ZIKV) is a flavivirus transmitted by mosquito vectors that leads to notable... (Review)
Review
Over the years, viral infections have caused severe illness in humans. Zika Virus (ZIKV) is a flavivirus transmitted by mosquito vectors that leads to notable neurological impairment, whose most dramatic impact is the Congenital ZIKV Syndrome (CZS). ZIKV targets neuronal precursor cells leading to apoptosis and further impairment of neuronal development, causing microcephaly, lissencephaly, ventriculomegaly, and calcifications. Several regulators of biological processes are involved in CZS development, and in this context, microRNAs (miRNAs) seem to have a fundamental role. miRNAs are important regulators of protein translation, as they form the RISC silencing complex and interact with complementary mRNA target sequences to further post-transcriptional repression. In this context, little is known about their participation in the pathogenesis of viral infections. In this review, we discuss how miRNAs could relate to ZIKV and other flavivirus infections.
Topics: Animals; Gene Regulatory Networks; Humans; Immunity; MicroRNAs; Virus Replication; Zika Virus; Zika Virus Infection
PubMed: 34696422
DOI: 10.3390/v13101992 -
Acta Veterinaria Scandinavica Jun 2020Lissencephaly is a brain malformation characterized by smooth and thickened cerebral surface, which may result in structural epilepsy. Lissencephaly is not common in...
BACKGROUND
Lissencephaly is a brain malformation characterized by smooth and thickened cerebral surface, which may result in structural epilepsy. Lissencephaly is not common in veterinary medicine. Here, we characterize the first cases of lissencephaly in four Shih Tzu dogs, including clinical presentations and findings of magnetic resonance imaging of lissencephaly and several concomitant brain malformations.
CASE PRESENTATION
Early-onset acute signs of forebrain abnormalities were observed in all dogs, which were mainly cluster seizures and behavioral alterations. Based on neurological examination, the findings were consistent with symmetrical and bilateral forebrain lesions. Metabolic disorders and inflammatory diseases were excluded. Magnetic resonance imaging for three dogs showed diffuse neocortical agyria and thickened gray matter while one dog had mixed agyria and pachygyria. Other features, such as internal hydrocephalus, supracollicular fluid accumulation, and corpus callosum hypoplasia, were detected concomitantly. Antiepileptic drugs effectively controlled cluster seizures, however, sporadic isolated seizures and signs of forebrain abnormalities, such as behavioral alterations, central blindness, and strabismus persisted.
CONCLUSIONS
Lissencephaly should be considered an important differential diagnosis in Shih Tzu dogs presenting with early-onset signs of forebrain abnormalities, including cluster seizures and behavioral alterations. Magnetic resonance imaging was appropriate for ante-mortem diagnosis of lissencephaly and associated cerebral anomalies.
Topics: Animals; Anticonvulsants; Dog Diseases; Dogs; Epilepsy; Female; Lissencephaly; Magnetic Resonance Imaging; Male
PubMed: 32563254
DOI: 10.1186/s13028-020-00528-0 -
The Neuroscientist : a Review Journal... Aug 2023The cerebral cortex develops through a carefully conscripted series of cellular and molecular events that culminate in the production of highly specialized neuronal and... (Review)
Review
The cerebral cortex develops through a carefully conscripted series of cellular and molecular events that culminate in the production of highly specialized neuronal and glial cells. During development, cortical neurons and glia acquire a precise cellular arrangement and architecture to support higher-order cognitive functioning. Decades of study using rodent models, naturally gyrencephalic animal models, human pathology specimens, and, recently, human cerebral organoids, reveal that rodents recapitulate some but not all the cellular and molecular features of human cortices. Whereas rodent cortices are smooth-surfaced or lissencephalic, larger mammals, including humans and nonhuman primates, have highly folded/gyrencephalic cortices that accommodate an expansion in neuronal mass and increase in surface area. Several genes have evolved to drive cortical gyrification, arising from gene duplications or de novo origins, or by alterations to the structure/function of ancestral genes or their gene regulatory regions. Primary cortical folds arise in stereotypical locations, prefigured by a molecular "blueprint" that is set up by several signaling pathways (e.g., Notch, Fgf, Wnt, PI3K, Shh) and influenced by the extracellular matrix. Mutations that affect neural progenitor cell proliferation and/or neurogenesis, predominantly of upper-layer neurons, perturb cortical gyrification. Below we review the molecular drivers of cortical folding and their roles in disease.
PubMed: 37621149
DOI: 10.1177/10738584231190839 -
Genetics in Medicine : Official Journal... Jul 2023Miller-Dieker syndrome is caused by a multiple gene deletion, including PAFAH1B1 and YWHAE. Although deletion of PAFAH1B1 causes lissencephaly unambiguously, deletion of... (Review)
Review
PURPOSE
Miller-Dieker syndrome is caused by a multiple gene deletion, including PAFAH1B1 and YWHAE. Although deletion of PAFAH1B1 causes lissencephaly unambiguously, deletion of YWHAE alone has not clearly been linked to a human disorder.
METHODS
Cases with YWHAE variants were collected through international data sharing networks. To address the specific impact of YWHAE loss of function, we phenotyped a mouse knockout of Ywhae.
RESULTS
We report a series of 10 individuals with heterozygous loss-of-function YWHAE variants (3 single-nucleotide variants and 7 deletions <1 Mb encompassing YWHAE but not PAFAH1B1), including 8 new cases and 2 follow-ups, added with 5 cases (copy number variants) from literature review. Although, until now, only 1 intragenic deletion has been described in YWHAE, we report 4 new variants specifically in YWHAE (3 splice variants and 1 intragenic deletion). The most frequent manifestations are developmental delay, delayed speech, seizures, and brain malformations, including corpus callosum hypoplasia, delayed myelination, and ventricular dilatation. Individuals with variants affecting YWHAE alone have milder features than those with larger deletions. Neuroanatomical studies in Ywhae mice revealed brain structural defects, including thin cerebral cortex, corpus callosum dysgenesis, and hydrocephalus paralleling those seen in humans.
CONCLUSION
This study further demonstrates that YWHAE loss-of-function variants cause a neurodevelopmental disease with brain abnormalities.
Topics: Humans; Animals; Mice; Brain; Lissencephaly; Neurodevelopmental Disorders; Classical Lissencephalies and Subcortical Band Heterotopias; Intellectual Disability; 14-3-3 Proteins
PubMed: 36999555
DOI: 10.1016/j.gim.2023.100835 -
Nature Communications May 2022Subcortical heterotopias are malformations associated with epilepsy and intellectual disability, characterized by the presence of ectopic neurons in the white matter....
Subcortical heterotopias are malformations associated with epilepsy and intellectual disability, characterized by the presence of ectopic neurons in the white matter. Mouse and human heterotopia mutations were identified in the microtubule-binding protein Echinoderm microtubule-associated protein-like 1, EML1. Further exploring pathological mechanisms, we identified a patient with an EML1-like phenotype and a novel genetic variation in DLGAP4. The protein belongs to a membrane-associated guanylate kinase family known to function in glutamate synapses. We showed that DLGAP4 is strongly expressed in the mouse ventricular zone (VZ) from early corticogenesis, and interacts with key VZ proteins including EML1. In utero electroporation of Dlgap4 knockdown (KD) and overexpression constructs revealed a ventricular surface phenotype including changes in progenitor cell dynamics, morphology, proliferation and neuronal migration defects. The Dlgap4 KD phenotype was rescued by wild-type but not mutant DLGAP4. Dlgap4 is required for the organization of radial glial cell adherens junction components and actin cytoskeleton dynamics at the apical domain, as well as during neuronal migration. Finally, Dlgap4 heterozygous knockout (KO) mice also show developmental defects in the dorsal telencephalon. We hence identify a synapse-related scaffold protein with pleiotropic functions, influencing the integrity of the developing cerebral cortex.
Topics: Animals; Cell Movement; Cerebral Cortex; Classical Lissencephalies and Subcortical Band Heterotopias; Humans; Mice; Mice, Knockout; Neurogenesis; Neurons; SAP90-PSD95 Associated Proteins
PubMed: 35585091
DOI: 10.1038/s41467-022-30443-z -
Cells Jan 2022The incidence of neurological disorders is increasing due to population growth and extended life expectancy. Despite advances in the understanding of these disorders,... (Review)
Review
BACKGROUND
The incidence of neurological disorders is increasing due to population growth and extended life expectancy. Despite advances in the understanding of these disorders, curative strategies for treatment have not yet eventuated. In part, this is due to the complexities of the disorders and a lack of identification of their specific underlying pathologies. has provided a useful, simple model to aid in unraveling the complex pathological characteristics of neurological disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, neuronal ceroid lipofuscinoses and lissencephaly. In addition, has proven to be an innovative model for pharmaceutical research in the neurological field.
SCOPE OF REVIEW
This review describes the contributions of in the field of neurological research. The continued exploration of proteins implicated in neurological disorders in may elucidate their pathological roles and fast-track curative therapeutics.
Topics: Dictyostelium; Humans; Huntington Disease; Models, Biological; Neuronal Ceroid-Lipofuscinoses; Proteins
PubMed: 35159273
DOI: 10.3390/cells11030463 -
Nature Communications Jun 2023Lissencephaly-1 (LIS1) is associated with neurodevelopmental diseases and is known to regulate the molecular motor cytoplasmic dynein activity. Here we show that LIS1 is...
Lissencephaly-1 (LIS1) is associated with neurodevelopmental diseases and is known to regulate the molecular motor cytoplasmic dynein activity. Here we show that LIS1 is essential for the viability of mouse embryonic stem cells (mESCs), and it governs the physical properties of these cells. LIS1 dosage substantially affects gene expression, and we uncovered an unexpected interaction of LIS1 with RNA and RNA-binding proteins, most prominently the Argonaute complex. We demonstrate that LIS1 overexpression partially rescued the extracellular matrix (ECM) expression and mechanosensitive genes conferring stiffness to Argonaute null mESCs. Collectively, our data transforms the current perspective on the roles of LIS1 in post-transcriptional regulation underlying development and mechanosensitive processes.
Topics: Animals; Mice; 1-Alkyl-2-acetylglycerophosphocholine Esterase; Blastocyst; Cell Survival; Embryo, Mammalian; Embryonic Stem Cells; Microtubule-Associated Proteins; Pluripotent Stem Cells; Protein Interaction Maps; Argonaute Proteins
PubMed: 37280197
DOI: 10.1038/s41467-023-38797-8 -
Translational Pediatrics Jan 2023During embryonic development, the dysregulation of the proliferation and differentiation of neuronal progenitors triggers congenital brain malformations. These... (Review)
Review
BACKGROUND AND OBJECTIVE
During embryonic development, the dysregulation of the proliferation and differentiation of neuronal progenitors triggers congenital brain malformations. These malformations are common causes of morbidity and mortality in patients younger than 2 years old. Animal models have provided considerable insights into the etiology of diseases that cause congenital brain malformations. However, the interspecies differences in brain structure limit the ability to transfer these insights directly to studies of humans. In recent years, brain organoids generated from human embryonic stem cells (hESCs) or human induced pluripotent stem cells (hiPSCs) using a 3-dimensional (3D) culture system have been used to resemble the structure and function of a developing human brain. Therefore, we aimed to summarize the different congenital brain malformations that have been modeled by organoids and discuss the ability of this model to reveal the cellular and molecular mechanisms of congenital brain malformations.
METHODS
A comprehensive search was performed using PubMed and Web of Science's Core Collection for literature published from July 1, 2000 to July 1, 2022. Keywords included terms related to brain organoids and congenital brain malformations, as well as names of individual malformations.
KEY CONTENT AND FINDINGS
The self-assembled 3D aggregates have been used to recapitulate structural malformations of human brains, such as microcephaly, macrocephaly, lissencephaly (LIS), and periventricular nodular heterotopia (PH). The use of disease-specific brain organoids has revealed unprecedented details of mechanisms that cause congenital brain malformations.
CONCLUSIONS
This review summarizes the establishment and development of brain organoid technologies and provides an overview of their applications in modeling congenital brain malformations. Although several hurdles still need to be overcome, using brain organoids has greatly expanded our ability to reveal the pathogenesis of congenital brain malformations. Compared with existing methods, the combination with cutting-edge technologies enables a more accurate diagnosis and development of increasingly personalized targeted therapy for patients with congenital brain diseases.
PubMed: 36798935
DOI: 10.21037/tp-22-239 -
Frontiers in Cellular Neuroscience 2023Microtubules are dynamic cytoskeletal structures involved in several cellular functions, such as intracellular trafficking, cell division and motility. More than other...
Microtubules are dynamic cytoskeletal structures involved in several cellular functions, such as intracellular trafficking, cell division and motility. More than other cell types, neurons rely on the proper functioning of microtubules to conduct their activities and achieve complex morphologies. Pathogenic variants in genes encoding for α and β-tubulins, the structural subunits of microtubules, give rise to a wide class of neurological disorders collectively known as "tubulinopathies" and mainly involving a wide and overlapping range of brain malformations resulting from defective neuronal proliferation, migration, differentiation and axon guidance. Although tubulin mutations have been classically linked to neurodevelopmental defects, growing evidence demonstrates that perturbations of tubulin functions and activities may also drive neurodegeneration. In this study, we causally link the previously unreported missense mutation p.I384N in TUBA1A, one of the neuron-specific α-tubulin isotype I, to a neurodegenerative disorder characterized by progressive spastic paraplegia and ataxia. We demonstrate that, in contrast to the p.R402H substitution, which is one of the most recurrent TUBA1A pathogenic variants associated to lissencephaly, the present mutation impairs TUBA1A stability, reducing the abundance of TUBA1A available in the cell and preventing its incorporation into microtubules. We also show that the isoleucine at position 384 is an amino acid residue, which is critical for α-tubulin stability, since the introduction of the p.I384N substitution in three different tubulin paralogs reduces their protein level and assembly into microtubules, increasing their propensity to aggregation. Moreover, we demonstrate that the inhibition of the proteasome degradative systems increases the protein levels of TUBA1A mutant, promoting the formation of tubulin aggregates that, as their size increases, coalesce into inclusions that precipitate within the insoluble cellular fraction. Overall, our data describe a novel pathogenic effect of p.I384N mutation that differs from the previously described substitutions in , and expand both phenotypic and mutational spectrum related to this gene.
PubMed: 37435044
DOI: 10.3389/fncel.2023.1162363