scholarly journals CNS glycosylphosphatidylinositol deficiency results in delayed white matter development, ataxia and premature death in a novel mouse model

2020 ◽  
Vol 29 (7) ◽  
pp. 1205-1217 ◽  
Author(s):  
Marshall Lukacs ◽  
Lauren E Blizzard ◽  
Rolf W Stottmann
Keyword(s):  
White Matter ◽  
Mouse Model ◽  
Critical Role ◽  
Premature Death ◽  
Post Translational Modification ◽  
Gpi Anchor ◽  
Wide Range ◽  
Affected Tissue ◽  
White Matter Development ◽  
The Central Nervous System

Abstract The glycosylphosphatidylinositol (GPI) anchor is a post-translational modification added to approximately 150 different proteins to facilitate proper membrane anchoring and trafficking to lipid rafts. Biosynthesis and remodeling of the GPI anchor requires the activity of over 20 distinct genes. Defects in the biosynthesis of GPI anchors in humans lead to inherited glycosylphosphatidylinositol deficiency (IGD). IGD patients display a wide range of phenotypes though the central nervous system (CNS) appears to be the most commonly affected tissue. A full understanding of the etiology of these phenotypes has been hampered by the lack of animal models due to embryonic lethality of GPI biosynthesis gene null mutants. Here we model IGD by genetically ablating GPI production in the CNS with a conditional mouse allele of phosphatidylinositol glycan anchor biosynthesis, class A (Piga) and Nestin-Cre. We find that the mutants do not have structural brain defects but do not survive past weaning. The mutants show progressive decline with severe ataxia consistent with defects in cerebellar development. We show that the mutants have reduced myelination and defective Purkinje cell development. Surprisingly, we found that Piga was expressed in a fairly restricted pattern in the early postnatal brain consistent with the defects we observed in our model. Thus, we have generated a novel mouse model of the neurological defects of IGD which demonstrates a critical role for GPI biosynthesis in cerebellar and white matter development.

scholarly journals CNS Glycosylphosphatidylinositol Deficiency Results in Delayed White Matter Development, Ataxia, and Premature Death in a Novel Mouse Model

2019 ◽  
Author(s):  
Marshall Lukacs ◽  
Rolf W. Stottmann
Keyword(s):  
White Matter ◽  
Mouse Model ◽  
Critical Role ◽  
Premature Death ◽  
Post Translational Modification ◽  
Gpi Anchor ◽  
Wide Range ◽  
Affected Tissue ◽  
White Matter Development ◽  
The Central Nervous System

AbstractThe Glycosylphosphatidylinositol (GPI) anchor is a post-translational modification added to approximately 150 different proteins to facilitate proper membrane anchoring and trafficking to lipid rafts. Biosynthesis and remodeling of the GPI anchor requires the activity of over twenty distinct genes. Defects in the biosynthesis of GPI anchors in humans leads to Inherited Glycosylphosphatidylinositol Deficiency (IGD). IGD patients display a wide range of phenotypes though the central nervous system (CNS) appears to be the most commonly affected tissue. A full understanding of the etiology of these phenotypes has been hampered by the lack of animal models due to embryonic lethality of GPI biosynthesis gene null mutants. Here we model IGD by genetically ablating GPI production in the CNS with a conditional mouse allele of phosphatidylinositol glycan anchor biosynthesis, class A (Piga) and Nestin-Cre. We find that the mutants do not have structural brain defects but do not survive past weaning. The mutants show progressive decline with severe ataxia consistent with defects in cerebellar development. We show the mutants have reduced myelination and defective Purkinje cell development. Surprisingly we found Piga was expressed in a fairly restricted pattern in the early postnatal brain consistent with the defects we observed in our model. Thus, we have generated a novel mouse model of the neurological defects of IGD which demonstrates a critical role for GPI biosynthesis in cerebellar and white matter development.

scholarly journals Defined neuronal populations drive fatal phenotype in a mouse model of Leigh syndrome

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Irene Bolea ◽  
Alejandro Gella ◽  
Elisenda Sanz ◽  
Patricia Prada-Dacasa ◽  
Fabien Menardy ◽  
...  
Keyword(s):  
Mouse Model ◽  
Critical Role ◽  
Leigh Syndrome ◽  
Early Death ◽  
Epileptic Seizures ◽  
Premature Death ◽  
Neuronal Firing ◽  
Cellular Mechanisms ◽  
Neuronal Populations ◽  
Respiratory Involvement

Mitochondrial deficits in energy production cause untreatable and fatal pathologies known as mitochondrial disease (MD). Central nervous system affectation is critical in Leigh Syndrome (LS), a common MD presentation, leading to motor and respiratory deficits, seizures and premature death. However, only specific neuronal populations are affected. Furthermore, their molecular identity and their contribution to the disease remains unknown. Here, using a mouse model of LS lacking the mitochondrial complex I subunit Ndufs4, we dissect the critical role of genetically-defined neuronal populations in LS progression. Ndufs4 inactivation in Vglut2-expressing glutamatergic neurons leads to decreased neuronal firing, brainstem inflammation, motor and respiratory deficits, and early death. In contrast, Ndufs4 deletion in GABAergic neurons causes basal ganglia inflammation without motor or respiratory involvement, but accompanied by hypothermia and severe epileptic seizures preceding death. These results provide novel insight in the cell type-specific contribution to the pathology, dissecting the underlying cellular mechanisms of MD.

scholarly journals Therapeutic targeting of protein S-acylation for the treatment of disease

2019 ◽  
Vol 48 (1) ◽  
pp. 281-290 ◽  
Author(s):  
Niall J. Fraser ◽  
Jacqueline Howie ◽  
Krzysztof J. Wypijewski ◽  
William Fuller
Keyword(s):  
Critical Role ◽  
Cardiac Contractility ◽  
Protein S ◽  
Biological Processes ◽  
Post Translational Modification ◽  
Target Proteins ◽  
Specific Target ◽  
Receptor Signalling ◽  
Therapeutic Drugs ◽  
Wide Range

The post-translational modification protein S-acylation (commonly known as palmitoylation) plays a critical role in regulating a wide range of biological processes including cell growth, cardiac contractility, synaptic plasticity, endocytosis, vesicle trafficking, membrane transport and biased-receptor signalling. As a consequence, zDHHC-protein acyl transferases (zDHHC-PATs), enzymes that catalyse the addition of fatty acid groups to specific cysteine residues on target proteins, and acyl proteins thioesterases, proteins that hydrolyse thioester linkages, are important pharmaceutical targets. At present, no therapeutic drugs have been developed that act by changing the palmitoylation status of specific target proteins. Here, we consider the role that palmitoylation plays in the development of diseases such as cancer and detail possible strategies for selectively manipulating the palmitoylation status of specific target proteins, a necessary first step towards developing clinically useful molecules for the treatment of disease.

scholarly journals CHIP as a therapeutic target for neurological diseases

2020 ◽  
Vol 11 (9) ◽  
Author(s):  
Shuo Zhang ◽  
Zheng-wei Hu ◽  
Cheng-yuan Mao ◽  
Chang-he Shi ◽  
Yu-ming Xu
Keyword(s):  
Therapeutic Target ◽  
Molecular Mechanisms ◽  
Neurological Diseases ◽  
Critical Role ◽  
Interacting Protein ◽  
Ubiquitin E3 Ligase ◽  
Promising Therapeutic Target ◽  
Wide Range ◽  
Range Of Functions ◽  
The Central Nervous System

Abstract Carboxy-terminus of Hsc70-interacting protein (CHIP) functions both as a molecular co-chaperone and ubiquitin E3 ligase playing a critical role in modulating the degradation of numerous chaperone-bound proteins. To date, it has been implicated in the regulation of numerous biological functions, including misfolded-protein refolding, autophagy, immunity, and necroptosis. Moreover, the ubiquitous expression of CHIP in the central nervous system suggests that it may be implicated in a wide range of functions in neurological diseases. Several recent studies of our laboratory and other groups have highlighted the beneficial role of CHIP in the pathogenesis of several neurological diseases. The objective of this review is to discuss the possible molecular mechanisms that contribute to the pathogenesis of neurological diseases in which CHIP has a pivotal role, such as stroke, intracerebral hemorrhage, Alzheimer’s disease, Parkinson’s disease, and polyglutamine diseases; furthermore, CHIP mutations could also cause neurodegenerative diseases. Based on the available literature, CHIP overexpression could serve as a promising therapeutic target for several neurological diseases.

scholarly journals Early Influences of Microbiota on White Matter Development in Germ-Free Piglets

2021 ◽  
Vol 15 ◽  
Author(s):  
Sadia Ahmed ◽  
Sierrah D. Travis ◽  
Francisca V. Díaz-Bahamonde ◽  
Demisha D. L. Porter ◽  
Sara N. Henry ◽  
...  
Keyword(s):  
White Matter ◽  
Developmental Trajectories ◽  
Critical Role ◽  
Autism Spectrum ◽  
Microbial Colonization ◽  
Swine Model ◽  
Sexually Dimorphic ◽  
Germ Free ◽  
Commensal Microbiota ◽  
White Matter Development

Abnormalities in the prefrontal cortex (PFC), as well as the underlying white matter (WM) tracts, lie at the intersection of many neurodevelopmental disorders. The influence of microorganisms on brain development has recently been brought into the clinical and research spotlight as alterations in commensal microbiota are implicated in such disorders, including autism spectrum disorders, schizophrenia, depression, and anxiety via the gut-brain axis. In addition, gut dysbiosis is common in preterm birth patients who often display diffuse WM injury and delayed WM maturation in critical tracts including those within the PFC and corpus callosum. Microbial colonization of the gut aligns with ongoing postnatal processes of oligodendrogenesis and the peak of brain myelination in humans; however, the influence of microbiota on gyral WM development remains elusive. Here, we develop and validate a neonatal germ-free swine model to address these issues, as piglets share key similarities in WM volume, developmental trajectories, and distribution to humans. We find significant region-specific reductions, and sexually dimorphic trends, in WM volume, oligodendrogenesis, and mature oligodendrocyte numbers in germ-free piglets during a key postnatal epoch of myelination. Our findings indicate that microbiota plays a critical role in promoting WM development during early life when the brain is vulnerable to environmental insults that can result in an array of disabilities manifesting later in life.

Heterogeneity and Proliferative and Differential Regulators of NG2-glia in Physiological and Pathological States

2020 ◽  
Vol 27 (37) ◽  
pp. 6384-6406 ◽  
Author(s):  
Zuo Zhang ◽  
Hongli Zhou ◽  
Jiyin Zhou
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Physiological State ◽  
Critical Role ◽  
Adult Brain ◽  
Pathological State ◽  
Peripheral Neurons ◽  
Neuronal Synapses ◽  
The Central Nervous System ◽  
Rapid Modulation

NG2-glia, also called Oligodendrocyte Precursor Cells (OPCs), account for approximately 5%-10% of the cells in the developing and adult brain and constitute the fifth major cell population in the central nervous system. NG2-glia express receptors and ion channels involved in rapid modulation of neuronal activities and signaling with neuronal synapses, which have functional significance in both physiological and pathological states. NG2-glia participate in quick signaling with peripheral neurons via direct synaptic touches in the developing and mature central nervous system. These distinctive glia perform the unique function of proliferating and differentiating into oligodendrocytes in the early developing brain, which is critical for axon myelin formation. In response to injury, NG2-glia can proliferate, migrate to the lesions, and differentiate into oligodendrocytes to form new myelin sheaths, which wrap around damaged axons and result in functional recovery. The capacity of NG2-glia to regulate their behavior and dynamics in response to neuronal activity and disease indicate their critical role in myelin preservation and remodeling in the physiological state and in repair in the pathological state. In this review, we provide a detailed summary of the characteristics of NG2-glia, including their heterogeneity, the regulators of their proliferation, and the modulators of their differentiation into oligodendrocytes.

Pathogenesis of Age-related Cataract: a systematic review of proteomic studies

2020 ◽  
Vol 17 ◽  
Author(s):  
Christina Karakosta ◽  
Argyrios Tzamalis ◽  
Michalis Aivaliotis ◽  
Ioannis Tsinopoulos
Keyword(s):  
Systematic Review ◽  
Oxidant Stress ◽  
Critical Role ◽  
Human Lens ◽  
Nuclear Cataract ◽  
Cataract Formation ◽  
Post Translational Modification ◽  
Ability To Act ◽  
Age Related

Background/Objective:: The aim of this systematic review is to identify all the available data on human lens proteomics with a critical role to age-related cataract formation in order to elucidate the physiopathology of the aging lens. Materials and Methods:: We searched on Medline and Cochrane databases. The search generated 328 manuscripts. We included nine original proteomic studies that investigated human cataractous lenses. Results:: Deamidation was the major age-related post-translational modification. There was a significant increase in the amount of αA-crystallin D-isoAsp58 present at all ages, while an increase in the extent of Trp oxidation was apparent in cataract lenses when compared to aged normal lenses. During aging, enzymes with oxidized cysteine at critical sites included GAPDH, glutathione synthase, aldehyde dehydrogenase, sorbitol dehydrogenase, and PARK7. Conclusion:: D-isoAsp in αA crystallin could be associated with the development of age-related cataract in human, by contributing to the denaturation of a crystallin, and decreasing its ability to act as a chaperone. Oxidation of Trp may be associated with nuclear cataract formation in human, while the role of oxidant stress in age-related cataract formation is dominant.

Shooting a Tiger

2018 ◽  
Author(s):  
Vijaya Ramadas Mandala
Keyword(s):  
Critical Role ◽  
Late Nineteenth Century ◽  
Way Of Life ◽  
Colonial India ◽  
British Raj ◽  
Early Colonial ◽  
Wide Range ◽  
Forest Legislation ◽  
Imperial Governance ◽  
North And South

The main contention of Shooting a Tiger is that hunting during the colonial period was not merely a recreational activity, but a practice intimately connected with imperial governance. The book positions shikar or hunting at the heart of colonial rule by demonstrating that, for the British in India, it served as a political, practical, and symbolic apparatus in the consolidation of power and rule during the nineteenth and early twentieth centuries. The book analyses early colonial hunting during the Company period, and then surveys different aspects of hunting during the high imperial decades in the later nineteenth and early twentieth centuries. The book draws upon an impressive array of archival material and uses a wide range of evidence to support its contentions. It examines hunting at a variety of social and ethnic levels—military, administrative, elite, princely India, Indian professional hunters, and in terms of Indian auxiliaries and (sometimes) resisters. It also deals with different geographical contexts—the plains, the mountains, north and south India. The exclusive privilege of hunting exercised by the ruling classes, following colonial forest legislation, continued to be extended to the Indian princes who played a critical role in sustaining the lavish hunts that became the hallmark of the late nineteenth-century British Raj. Hunting was also a way of life in colonial India, undertaken by officials and soldiers alike alongside their everyday duties, necessary for their mental sustenance and vital for the smooth operation of the colonial administration. There are also two final chapters on conservation, particularly the last chapter focusing on two British hunter-turned-conservationists, Jim Corbett and Colonel Richard Burton.

scholarly journals SARS-CoV-2 and the Nervous System: From Clinical Features to Molecular Mechanisms

2020 ◽  
Vol 21 (15) ◽  
pp. 5475 ◽  
Author(s):  
Manuela Pennisi ◽  
Giuseppe Lanza ◽  
Luca Falzone ◽  
Francesco Fisicaro ◽  
Raffaele Ferri ◽  
...  
Keyword(s):  
Nervous System ◽  
Molecular Mechanisms ◽  
Neuronal Damage ◽  
Neurological Complications ◽  
Neurological Manifestations ◽  
Wide Range ◽  
Inflammatory State ◽  
Acute Polyneuropathy ◽  
The Central Nervous System ◽  
The Impact

Increasing evidence suggests that Severe Acute Respiratory Syndrome-coronavirus-2 (SARS-CoV-2) can also invade the central nervous system (CNS). However, findings available on its neurological manifestations and their pathogenic mechanisms have not yet been systematically addressed. A literature search on neurological complications reported in patients with COVID-19 until June 2020 produced a total of 23 studies. Overall, these papers report that patients may exhibit a wide range of neurological manifestations, including encephalopathy, encephalitis, seizures, cerebrovascular events, acute polyneuropathy, headache, hypogeusia, and hyposmia, as well as some non-specific symptoms. Whether these features can be an indirect and unspecific consequence of the pulmonary disease or a generalized inflammatory state on the CNS remains to be determined; also, they may rather reflect direct SARS-CoV-2-related neuronal damage. Hematogenous versus transsynaptic propagation, the role of the angiotensin II converting enzyme receptor-2, the spread across the blood-brain barrier, the impact of the hyperimmune response (the so-called “cytokine storm”), and the possibility of virus persistence within some CNS resident cells are still debated. The different levels and severity of neurotropism and neurovirulence in patients with COVID-19 might be explained by a combination of viral and host factors and by their interaction.

scholarly journals Collagen molecular phenotypic switch between non-neoplastic and neoplastic canine mammary tissues

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Masahiko Terajima ◽  
Yuki Taga ◽  
Becky K. Brisson ◽  
Amy C. Durham ◽  
Kotaro Sato ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mammary Gland ◽  
Mammary Carcinoma ◽  
Cancer Biology ◽  
Type I Collagen ◽  
Critical Role ◽  
Premature Death ◽  
Mammary Tissue ◽  
Type I ◽  
Cross Links

AbstractIn spite of major advances over the past several decades in diagnosis and treatment, breast cancer remains a global cause of morbidity and premature death for both human and veterinary patients. Due to multiple shared clinicopathological features, dogs provide an excellent model of human breast cancer, thus, a comparative oncology approach may advance our understanding of breast cancer biology and improve patient outcomes. Despite an increasing awareness of the critical role of fibrillar collagens in breast cancer biology, tumor-permissive collagen features are still ill-defined. Here, we characterize the molecular and morphological phenotypes of type I collagen in canine mammary gland tumors. Canine mammary carcinoma samples contained longer collagen fibers as well as a greater population of wider fibers compared to non-neoplastic and adenoma samples. Furthermore, the total number of collagen cross-links enriched in the stable hydroxylysine-aldehyde derived cross-links was significantly increased in neoplastic mammary gland samples compared to non-neoplastic mammary gland tissue. The mass spectrometric analyses of type I collagen revealed that in malignant mammary tumor samples, lysine residues, in particular those in the telopeptides, were markedly over-hydroxylated in comparison to non-neoplastic mammary tissue. The extent of glycosylation of hydroxylysine residues was comparable among the groups. Consistent with these data, expression levels of genes encoding lysyl hydroxylase 2 (LH2) and its molecular chaperone FK506-binding protein 65 were both significantly increased in neoplastic samples. These alterations likely lead to an increase in the LH2-mediated stable collagen cross-links in mammary carcinoma that may promote tumor cell metastasis in these patients.

Sign in / Sign up

Export Citation Format

Share Document