scholarly journals Dystroglycanopathy: From Elucidation of Molecular and Pathological Mechanisms to Development of Treatment Methods

2021 ◽  
Vol 22 (23) ◽  
pp. 13162
Author(s):  
Motoi Kanagawa
Keyword(s):  
Clinical Symptoms ◽  
Treatment Strategies ◽  
Chain Structure ◽  
Gene Products ◽  
Therapeutic Approaches ◽  
Causative Gene ◽  
Sugar Chain ◽  
The Central Nervous System ◽  
Sugar Chains ◽  
Abnormal Glycosylation

Dystroglycanopathy is a collective term referring to muscular dystrophies with abnormal glycosylation of dystroglycan. At least 18 causative genes of dystroglycanopathy have been identified, and its clinical symptoms are diverse, ranging from severe congenital to adult-onset limb-girdle types. Moreover, some cases are associated with symptoms involving the central nervous system. In the 2010s, the structure of sugar chains involved in the onset of dystroglycanopathy and the functions of its causative gene products began to be identified as if they were filling the missing pieces of a jigsaw puzzle. In parallel with these discoveries, various dystroglycanopathy model mice had been created, which led to the elucidation of its pathological mechanisms. Then, treatment strategies based on the molecular basis of glycosylation began to be proposed after the latter half of the 2010s. This review briefly explains the sugar chain structure of dystroglycan and the functions of the causative gene products of dystroglycanopathy, followed by introducing the pathological mechanisms involved as revealed from analyses of dystroglycanopathy model mice. Finally, potential therapeutic approaches based on the pathological mechanisms involved are discussed.

Healthy Gut, Healthy Brain: The Gut Microbiome in Neurodegenerative Disorders

2020 ◽  
Vol 20 (13) ◽  
pp. 1142-1153 ◽  
Author(s):  
Sreyashi Chandra ◽  
Md. Tanjim Alam ◽  
Jhilik Dey ◽  
Baby C. Pulikkaparambil Sasidharan ◽  
Upasana Ray ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Neurodegenerative Disorders ◽  
The Body ◽  
Therapeutic Approaches ◽  
Cns Disorders ◽  
Physiological Conditions ◽  
Pathological Conditions ◽  
The Central Nervous System ◽  
Present Understanding ◽  
Lateral Sclerosis

Background: The central nervous system (CNS) known to regulate the physiological conditions of human body, also itself gets dynamically regulated by both the physiological as well as pathological conditions of the body. These conditions get changed quite often, and often involve changes introduced into the gut microbiota which, as studies are revealing, directly modulate the CNS via a crosstalk. This cross-talk between the gut microbiota and CNS, i.e., the gut-brain axis (GBA), plays a major role in the pathogenesis of many neurodegenerative disorders such as Parkinson’s disease (PD), Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and Huntington’s disease (HD). Objective: We aim to discuss how gut microbiota, through GBA, regulate neurodegenerative disorders such as PD, AD, ALS, MS and HD. Methods: In this review, we have discussed the present understanding of the role played by the gut microbiota in neurodegenerative disorders and emphasized the probable therapeutic approaches being explored to treat them. Results: In the first part, we introduce the GBA and its relevance, followed by the changes occurring in the GBA during neurodegenerative disorders and then further discuss its role in the pathogenesis of these diseases. Finally, we discuss its applications in possible therapeutics of these diseases and the current research improvements being made to better investigate this interaction. Conclusion: We concluded that alterations in the intestinal microbiota modulate various activities that could potentially lead to CNS disorders through interactions via the GBA.

scholarly journals Comparison of Genetic Variants and Manifestations of OTUD6B-Related Disorder: The First Mexican Case

2020 ◽  
Vol 8 ◽  
pp. 232470962095777 ◽  
Author(s):  
Maria Elena Romero-Ibarguengoitia ◽  
Consuelo Cantú-Reyna ◽  
Dalia Gutierrez-González ◽  
Héctor Cruz-Camino ◽  
Arnulfo González-Cantú ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Genetic Variants ◽  
Therapeutic Approaches ◽  
Multisystem Disorder ◽  
Related Disorder ◽  
Dysmorphic Features ◽  
The Third ◽  
The Central Nervous System ◽  
Mexican Patient

The intellectual disability syndrome characterized by seizures and dysmorphic features was initially described in 2017 and was associated with genetic variants in the OTUD6B gene, identified by exome sequencing (ES) in a large cohort. This multisystem disorder primarily affects the central nervous system, the gastrointestinal, and the skeletal systems. In this article, we describe the first Mexican patient diagnosed by ES. The homozygous c.433C>T (p.Arg145*) variant of the OTUD6B gene confirmed this intellectual disability syndrome. In addition to seizures and other more frequently reported manifestations of this condition, this is the third patient with associated hypothyroidism and hypogammaglobulinemia, underscoring the value of screening for these conditions in other patients. The current challenge with this patient is to ensure medical management of his seizures and provide him with a better quality of life. The possibilities of additional therapeutic approaches may increase by understanding the physiopathology of the involved pathways.

scholarly journals Neuroinflammation and the Kynurenine Pathway in CNS Disease: Molecular Mechanisms and Therapeutic Implications

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1548
Author(s):  
Mustafa N. Mithaiwala ◽  
Danielle Santana-Coelho ◽  
Grace A. Porter ◽  
Jason C. O’Connor
Keyword(s):  
Molecular Mechanisms ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Kynurenine Pathway ◽  
Economic Problem ◽  
Cns Disease ◽  
Therapeutic Implications ◽  
Efficacious Treatment ◽  
The Central Nervous System ◽  
Significant Health

Diseases of the central nervous system (CNS) remain a significant health, social and economic problem around the globe. The development of therapeutic strategies for CNS conditions has suffered due to a poor understanding of the underlying pathologies that manifest them. Understanding common etiological origins at the cellular and molecular level is essential to enhance the development of efficacious and targeted treatment options. Over the years, neuroinflammation has been posited as a common link between multiple neurological, neurodegenerative and neuropsychiatric disorders. Processes that precipitate neuroinflammatory conditions including genetics, infections, physical injury and psychosocial factors, like stress and trauma, closely link dysregulation in kynurenine pathway (KP) of tryptophan metabolism as a possible pathophysiological factor that ‘fuel the fire’ in CNS diseases. In this study, we aim to review emerging evidence that provide mechanistic insights between different CNS disorders, neuroinflammation and the KP. We provide a thorough overview of the different branches of the KP pertinent to CNS disease pathology that have therapeutic implications for the development of selected and efficacious treatment strategies.

Neuronal intranuclear hyaline inclusion disease is a neurodegenerative condition which can be a target for gene therapy

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Gene Therapy ◽  
Clinical Symptoms ◽  
Repeat Expansion ◽  
Gene Identification ◽  
Therapeutic Assessment ◽  
Causative Gene ◽  
Central Nervous System Disorders ◽  
Number Of Patients ◽  
Mechanism Research ◽  
Or Gene

NIHID (neuronal intranuclear hyaline inclusion disease) is a neurodegenerative condition that is easy to detect but also easy to misdiagnose. Thanks to breakthroughs in MRI detection, the availability of skin biopsied pathology, and, most critically, the finding of the causative gene which can be targeted by gene therapy, the rate of NIID diagnosis before death has grown significantly in recent years. Symptoms linked with central nervous system disorders, autonomic and peripheral neuropathy, and myopathy may be experienced by patients with NIID. Regardless of how far clinical symptoms or gene identification have progressed in NOTCH2NLC gene-related repeat expansion disorders (NRED), it not only adds to our understanding of NIID, but it also adds to the number of challenges we must address. East Asia has seen a substantial number of patients with GGC repeat expansion in NOTCH2NLC. Clinicians should work together to develop a database of NIID clinical and biological samples, as well as perform additional clinical diagnostic, therapeutic assessment, and pathogenic mechanism research.

scholarly journals Therapeutic Effects of Hydrogen in Animal Models of Parkinson's Disease

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Kyota Fujita ◽  
Yusaku Nakabeppu ◽  
Mami Noda
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Animal Models ◽  
Animal Studies ◽  
Clinical Symptoms ◽  
Therapeutic Effects ◽  
Therapeutic Approaches ◽  
Cellular Apoptosis ◽  
6 Hydroxydopamine

Since the first description of Parkinson's disease (PD) nearly two centuries ago, a number of studies have revealed the clinical symptoms, pathology, and therapeutic approaches to overcome this intractable neurodegenerative disease. 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) are neurotoxins which produce Parkinsonian pathology. From the animal studies using these neurotoxins, it has become well established that oxidative stress is a primary cause of, and essential for, cellular apoptosis in dopaminergic neurons. Here, we describe the mechanism whereby oxidative stress evokes irreversible cell death, and propose a novel therapeutic strategy for PD using molecular hydrogen. Hydrogen has an ability to reduce oxidative damage and ameliorate the loss of nigrostriatal dopaminergic neuronal pathway in two experimental animal models. Thus, it is strongly suggested that hydrogen might provide a great advantage to prevent or minimize the onset and progression of PD.

Primary Leptomeningeal Gliomatosis in Children and Adults: A Morphological and Molecular Comparative Study With Literature Review

Neurosurgery ◽  
2015 ◽  
Vol 78 (3) ◽  
pp. 343-352 ◽  
Author(s):  
Arnault Tauziede-Espariat ◽  
Andre Maues de Paula ◽  
Melanie Pages ◽  
Annie Laquerriere ◽  
Emilie Caietta ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Overall Survival ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Clinical Symptoms ◽  
Malignant Gliomas ◽  
Leptomeningeal Gliomatosis ◽  
Molecular Features ◽  
The Central Nervous System ◽  
The Mean

Abstract BACKGROUND: Primary leptomeningeal gliomatosis (PLG) is a poorly recognized tumor of the central nervous system. OBJECTIVE: To describe the histopathological, immunohistochemical, and molecular features of PLG. METHODS: Results of our multicentric retrospective study of 6 PLG cases (3 pediatric and 3 adult) were compared with literature data. RESULTS: The mean age was 54.7 years for adults and 8.7 years for children, with 3 males and 3 females. Clinical symptoms were nonspecific. Cerebrospinal fluid analyses showed a high protein level often associated with pleocytosis but without neoplastic cells. On neuroimaging, diffuse leptomeningeal enhancement and hydrocephalus were observed, except in 1 case. PLG was mostly misinterpreted as infectious or tumoral meningitis. The first biopsy was negative in 50% of cases. Histopathologically, PLG cases corresponded to 1 oligodendroglioma without 1p19q codeletion and 5 astrocytomas without expression of p53. No immunostaining for IDH1R132H and no mutations of IDH1/2 and H3F3A genes were found. Overall survival was highly variable (2-82 months) but seems to be increased in children treated with chemotherapy. CONCLUSION: This study shows the difficulties of PLG diagnosis. The challenge is to achieve an early biopsy to establish a diagnosis and to begin a treatment, but the prognosis remains poor. PLG seems to have a different molecular and immunohistochemical pattern compared with intraparenchymal malignant gliomas.

scholarly journals Regional CNS responses to IFN-γ determine lesion localization patterns during EAE pathogenesis

2008 ◽  
Vol 205 (11) ◽  
pp. 2633-2642 ◽  
Author(s):  
Jason R. Lees ◽  
Paul T. Golumbek ◽  
Julia Sim ◽  
Denise Dorsey ◽  
John H. Russell
Keyword(s):  
Spinal Cord ◽  
T Cells ◽  
Brain Stem ◽  
Clinical Outcomes ◽  
Clinical Symptoms ◽  
Inflammatory Cells ◽  
Th1 Cells ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Ifn Γ

The localization of inflammatory foci within the cerebellum is correlated to severe clinical outcomes in multiple sclerosis (MS). Previous studies of experimental autoimmune encephalomyelitis (EAE), a model of MS, revealed distinct clinical outcomes correlated with the capacity of the animal to produce IFN-γ. Outcomes were linked to localization of inflammatory cells in either the spinal cord (wild type [WT]) or the cerebellum and brain stem (IFN-γ deficient). We demonstrate, using an adoptive transfer system, that the ability of the central nervous system (CNS) to sense pathogenic T cell–produced IFN-γ during EAE initiation determines the sites of CNS pathogenesis. Transfer of WT Th1 cells into IFN-γ receptor–deficient mice results in pathogenic invasion of the brain stem and cerebellum with attendant clinical symptoms, which are identical to the disease observed after transfer of IFN-γ–deficient T cells to WT hosts. Inflammation of the spinal cord associated with classical EAE is abrogated in both IFN-γ–deficient systems. Cotransfer of CNS antigen-specific WT Th1 cells with IFN-γ–deficient T cells is sufficient to restore spinal cord invasion and block cerebellar and brain stem invasion. These data demonstrate that interaction between IFN-γ and host CNS cells during the initiation of EAE can selectively promote or suppress neuroinflammation and pathogenesis.

MYRF haploinsufficiency causes 46,XY and 46,XX disorders of sex development: bioinformatics consideration

2019 ◽  
Vol 28 (14) ◽  
pp. 2319-2329 ◽  
Author(s):  
Kohei Hamanaka ◽  
Atsushi Takata ◽  
Yuri Uchiyama ◽  
Satoko Miyatake ◽  
Noriko Miyake ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Target Genes ◽  
De Novo ◽  
Clinical Symptoms ◽  
Disorders Of Sex Development ◽  
Sequencing Data ◽  
Causative Gene ◽  
Sex Development ◽  
And Migration ◽  
Proliferation And Migration

AbstractDisorders of sex development (DSDs) are defined as congenital conditions in which chromosomal, gonadal or anatomical sex is atypical. In many DSD cases, genetic causes remain to be elucidated. Here, we performed a case–control exome sequencing study comparing gene-based burdens of rare damaging variants between 26 DSD cases and 2625 controls. We found exome-wide significant enrichment of rare heterozygous truncating variants in the MYRF gene encoding myelin regulatory factor, a transcription factor essential for oligodendrocyte development. All three variants occurred de novo. We identified an additional 46,XY DSD case of a de novo damaging missense variant in an independent cohort. The clinical symptoms included hypoplasia of Müllerian derivatives and ovaries in 46,XX DSD patients, defective development of Sertoli and Leydig cells in 46,XY DSD patients and congenital diaphragmatic hernia in one 46,XY DSD patient. As all of these cells and tissues are or partly consist of coelomic epithelium (CE)-derived cells (CEDC) and CEDC developed from CE via proliferaiton and migration, MYRF might be related to these processes. Consistent with this hypothesis, single-cell RNA sequencing of foetal gonads revealed high expression of MYRF in CE and CEDC. Reanalysis of public chromatin immunoprecipitation sequencing data for rat Myrf showed that genes regulating proliferation and migration were enriched among putative target genes of Myrf. These results suggested that MYRF is a novel causative gene of 46,XY and 46,XX DSD and MYRF is a transcription factor regulating CD and/or CEDC proliferation and migration, which is essential for development of multiple organs.

scholarly journals Two Cases of Anomalous Origin of Left Coronary Artery From The Pulmonary Artery

2021 ◽  
Author(s):  
Zhao Juan ◽  
Zou Chunbo
Keyword(s):  
Coronary Artery ◽  
Pulmonary Artery ◽  
Vascular Malformation ◽  
Left Coronary Artery ◽  
Clinical Symptoms ◽  
Treatment Strategies ◽  
Anomalous Origin ◽  
Coronary Cta ◽  
Congenital Vascular Malformation

Abstract Coronary artery originating from pulmonary artery is a rare congenital vascular malformation, which generally presents corresponding clinical symptoms with the growth of patients' age. Coronary CTA and angiography are important methods for diagnosis of this disease, and provide evidence for treatment strategies of patients.

The efficiency of N-linked glycosylation of bovine DNase I depends on the Asn-Xaa-Ser/Thr sequence and the tissue of origin

2001 ◽  
Vol 355 (1) ◽  
pp. 245-248 ◽  
Author(s):  
Atsushi NISHIKAWA ◽  
Sumi MIZUNO
Keyword(s):  
Submaxillary Gland ◽  
Dnase I ◽  
The State ◽  
Sugar Chain ◽  
Glycosylation Sites ◽  
Tissue Of Origin ◽  
Sugar Chains

Bovine DNase I contains two potential N-linked glycosylation sites with the sequences Asn18-Ala-Thr and Asn106-Asp-Ser. A previous report established that pancreatic DNase I has only one sugar chain at Asn18 [Liao, Salnikow, Moore and Stein (1973) J. Biol. Chem. 248, 1489–1495]. We found, however, that bovine DNase I expressed in COS-1 cells was glycosylated about 70% at Asn106 in addition to being completely glycosylated at Asn18. Glycosylation of Asn106 increased to 97% when Asp107 was mutated to Glu or when Ser108 was mutated to Thr. Mutation of Asp107 to Trp had no effect, whereas a substitution with Pro at this position abolished glycosylation of Asn106. Analysis of the state of glycosylation of DNase I purified from a variety of bovine tissues revealed that DNase I from spleen, submaxillary gland, lung and adrenal had two sugar chains, whereas enzyme from pancreas and kidney had only one sugar chain. These findings demonstrate a major difference in the ability of various tissues to utilize N-linked glycosylation signals that contain suboptimal residues in the second and third positions.

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