scholarly journals PP1C and PP2A are p70S6K Phosphatases Whose Inhibition Ameliorates HLD12-Associated Inhibition of Oligodendroglial Cell Morphological Differentiation

Biomedicines ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 89
Author(s):  
Naoto Matsumoto ◽  
Yuki Miyamoto ◽  
Kohei Hattori ◽  
Akihiro Ito ◽  
Hironori Harada ◽  
...  
Keyword(s):  
Protein Trafficking ◽  
Morphological Differentiation ◽  
Autosomal Recessive Disorder ◽  
Kinase Activation ◽  
Oligodendroglial Cell ◽  
Pathological Mechanism ◽  
Molecular Group ◽  
The Central Nervous System ◽  
Vacuolar Protein ◽  
Pelizaeus Merzbacher Disease

Myelin sheaths created by oligodendroglial cells encase neuronal axons to achieve saltatory conduction and protect axons. Pelizaeus-Merzbacher disease (PMD) is a prototypic, hereditary demyelinating oligodendroglial disease of the central nervous system (CNS), and is currently known as hypomyelinating leukodystrophy 1 (HLD1). HLD12 is an autosomal recessive disorder responsible for the gene that encodes vacuolar protein sorting-associated protein 11 homolog (VPS11). VPS11 is a member of the molecular group controlling the early endosome antigen 1 (EEA1)- and Rab7-positive vesicle-mediated protein trafficking to the lysosomal compartments. Herein, we show that the HLD12-associated Cys846-to-Gly (C846G) mutation of VPS11 leads to its aggregate formation with downregulated signaling through 70 kDa S6 protein kinase (p70S6K) in the oligodendroglial cell line FBD-102b as the model. In contrast, wild-type proteins are localized in both EEA1- and Rab7-positive vesicles. Cells harboring the C846G mutant constructs decrease differentiated phenotypes with web-like structures following differentiation, whereas parental cells exhibit them suitably. It is of note that we identify PP1C and PP2A as the protein phosphatases for phosphorylated Thr-389 of p70S6K essential for kinase activation in cells. The respective knockdown experiments or inhibitor treatment stimulates phosphorylation of p70S6K and ameliorates the inhibition of morphological differentiation, as well as the formation of protein aggregates. These results indicate that inhibition of p70S6K phosphatases PP1C and PP2A improves the defective morphological differentiation associated with HLD12 mutation, thereby hinting at amelioration based on a possible molecular and cellular pathological mechanism underlying HLD12.

scholarly journals Coupling of terminal differentiation deficit with neurodegenerative pathology in Vps35-deficient pyramidal neurons

2020 ◽  
Vol 27 (7) ◽  
pp. 2099-2116 ◽  
Author(s):  
Fu-Lei Tang ◽  
Lu Zhao ◽  
Yang Zhao ◽  
Dong Sun ◽  
Xiao-Juan Zhu ◽  
...  
Keyword(s):  
Protein Trafficking ◽  
Pyramidal Neurons ◽  
Transmembrane Protein ◽  
Terminal Differentiation ◽  
Physiological Role ◽  
Neurodegenerative Pathology ◽  
Associated Proteins ◽  
Developing Neurons ◽  
Vacuolar Protein ◽  
Embryonic Neurons

AbstractVps35 (vacuolar protein sorting 35) is a key component of retromer that regulates transmembrane protein trafficking. Dysfunctional Vps35 is a risk factor for neurodegenerative diseases, including Parkinson’s and Alzheimer’s diseases. Vps35 is highly expressed in developing pyramidal neurons, and its physiological role in developing neurons remains to be explored. Here, we provide evidence that Vps35 in embryonic neurons is necessary for axonal and dendritic terminal differentiation. Loss of Vps35 in embryonic neurons results in not only terminal differentiation deficits, but also neurodegenerative pathology, such as cortical brain atrophy and reactive glial responses. The atrophy of neocortex appears to be in association with increases in neuronal death, autophagosome proteins (LC3-II and P62), and neurodegeneration associated proteins (TDP43 and ubiquitin-conjugated proteins). Further studies reveal an increase of retromer cargo protein, sortilin1 (Sort1), in lysosomes of Vps35-KO neurons, and lysosomal dysfunction. Suppression of Sort1 diminishes Vps35-KO-induced dendritic defects. Expression of lysosomal Sort1 recapitulates Vps35-KO-induced phenotypes. Together, these results demonstrate embryonic neuronal Vps35’s function in terminal axonal and dendritic differentiation, reveal an association of terminal differentiation deficit with neurodegenerative pathology, and uncover an important lysosomal contribution to both events.

Hermansky–Pudlak Syndrome

2020 ◽  
Vol 41 (02) ◽  
pp. 238-246
Author(s):  
Wilfredo De Jesus Rojas ◽  
Lisa R. Young
Keyword(s):  
Protein Trafficking ◽  
Health Management ◽  
Treatment Options ◽  
Clinical Manifestations ◽  
Autosomal Recessive Disorder ◽  
Oculocutaneous Albinism ◽  
Clinical Approach ◽  
Recessive Mutations ◽  
Hermansky Pudlak Syndrome ◽  
Traction Bronchiectasis

AbstractHermansky–Pudlak syndrome (HPS) is a multisystemic autosomal recessive disorder characterized by oculocutaneous albinism, bleeding diathesis, and lethal pulmonary fibrosis (PF) in some HPS subtypes. During middle adulthood, ground-glass opacities, reticulation, and traction bronchiectasis develop with progression of PF. HPS is an orphan disease occurring in 1 in 500,000 to 1,000,000 individuals worldwide, though the prevalence is 1 in 1,800 in individuals with Puerto Rican heritage. Recessive mutations or disruptions in HPS genes alter the function of HPS proteins which are components of biogenesis of lysosome-related organelle complexes and are critical for intracellular protein trafficking. Diagnosis and management of HPS-related comorbidities represent a challenge to physicians, and a multidisciplinary clinical approach is necessary for early detection, health management, and surveillance of PF in patients with HPS types 1, 2, and 4. Treatment options for individuals with HPS-PF include pirfenidone and lung transplantation. In this article, we describe the epidemiology, genetics, clinical manifestations, and management of HPS.

scholarly journals Prion and Prion-Like Protein Strains: Deciphering the Molecular Basis of Heterogeneity in Neurodegeneration

Viruses ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 261 ◽  
Author(s):  
Carlo Scialò ◽  
Elena De Cecco ◽  
Paolo Manganotti ◽  
Giuseppe Legname
Keyword(s):  
Neurodegenerative Disorders ◽  
Molecular Basis ◽  
Amyloid Β ◽  
Dna Binding Protein ◽  
Propagation Process ◽  
Replication Process ◽  
Therapeutic Implications ◽  
Pathological Mechanism ◽  
The Central Nervous System ◽  
Related Proteins

Increasing evidence suggests that neurodegenerative disorders share a common pathogenic feature: the presence of deposits of misfolded proteins with altered physicochemical properties in the Central Nervous System. Despite a lack of infectivity, experimental data show that the replication and propagation of neurodegenerative disease-related proteins including amyloid-β (Aβ), tau, α-synuclein and the transactive response DNA-binding protein of 43 kDa (TDP-43) share a similar pathological mechanism with prions. These observations have led to the terminology of “prion-like” to distinguish between conditions with noninfectious characteristics but similarities with the prion replication and propagation process. Prions are considered to adapt their conformation to changes in the context of the environment of replication. This process is known as either prion selection or adaptation, where a distinct conformer present in the initial prion population with higher propensity to propagate in the new environment is able to prevail over the others during the replication process. In the last years, many studies have shown that prion-like proteins share not only the prion replication paradigm but also the specific ability to aggregate in different conformations, i.e., strains, with relevant clinical, diagnostic and therapeutic implications. This review focuses on the molecular basis of the strain phenomenon in prion and prion-like proteins.

scholarly journals Characterization of a Novel Yeast SNARE Protein Implicated in Golgi Retrograde Traffic

1997 ◽  
Vol 8 (12) ◽  
pp. 2659-2676 ◽  
Author(s):  
Vladimir V. Lupashin ◽  
Irina D. Pokrovskaya ◽  
James A. McNew ◽  
M. Gerard Waters
Keyword(s):  
Protein Trafficking ◽  
Sequence Similarity ◽  
Integral Membrane Protein ◽  
Growth Defect ◽  
Carboxypeptidase Y ◽  
Temperature Sensitive ◽  
Snare Protein ◽  
Yeast Viability ◽  
Vacuolar Protein

The protein trafficking machinery of eukaryotic cells is employed for protein secretion and for the localization of resident proteins of the exocytic and endocytic pathways. Protein transit between organelles is mediated by transport vesicles that bear integral membrane proteins (v-SNAREs) which selectively interact with similar proteins on the target membrane (t-SNAREs), resulting in a docked vesicle. A novelSaccharomyces cerevisiae SNARE protein, which has been termed Vti1p, was identified by its sequence similarity to known SNAREs. Vti1p is a predominantly Golgi-localized 25-kDa type II integral membrane protein that is essential for yeast viability. Vti1p can bind Sec17p (yeast SNAP) and enter into a Sec18p (NSF)-sensitive complex with the cis-Golgi t-SNARE Sed5p. This Sed5p/Vti1p complex is distinct from the previously described Sed5p/Sec22p anterograde vesicle docking complex. Depletion of Vti1p in vivo causes a defect in the transport of the vacuolar protein carboxypeptidase Y through the Golgi. Temperature-sensitive mutants of Vti1p show a similar carboxypeptidase Y trafficking defect, but the secretion of invertase and gp400/hsp150 is not significantly affected. The temperature-sensitive vti1 growth defect can be rescued by the overexpression of the v-SNARE, Ykt6p, which physically interacts with Vti1p. We propose that Vti1p, along with Ykt6p and perhaps Sft1p, acts as a retrograde v-SNARE capable of interacting with the cis-Golgi t-SNARE Sed5p.

Biology of Oligodendrocyte and Myelin in the Mammalian Central Nervous System

2001 ◽  
Vol 81 (2) ◽  
pp. 871-927 ◽  
Author(s):  
Nicole Baumann ◽  
Danielle Pham-Dinh
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Proteolipid Protein ◽  
Demyelinating Diseases ◽  
Neural Cells ◽  
The Central Nervous System ◽  
Experimental Demyelination ◽  
Pelizaeus Merzbacher Disease ◽  
Spontaneous Mutants ◽  
Extracellular Environment

Oligodendrocytes, the myelin-forming cells of the central nervous system (CNS), and astrocytes constitute macroglia. This review deals with the recent progress related to the origin and differentiation of the oligodendrocytes, their relationships to other neural cells, and functional neuroglial interactions under physiological conditions and in demyelinating diseases. One of the problems in studies of the CNS is to find components, i.e., markers, for the identification of the different cells, in intact tissues or cultures. In recent years, specific biochemical, immunological, and molecular markers have been identified. Many components specific to differentiating oligodendrocytes and to myelin are now available to aid their study. Transgenic mice and spontaneous mutants have led to a better understanding of the targets of specific dys- or demyelinating diseases. The best examples are the studies concerning the effects of the mutations affecting the most abundant protein in the central nervous myelin, the proteolipid protein, which lead to dysmyelinating diseases in animals and human (jimpy mutation and Pelizaeus-Merzbacher disease or spastic paraplegia, respectively). Oligodendrocytes, as astrocytes, are able to respond to changes in the cellular and extracellular environment, possibly in relation to a glial network. There is also a remarkable plasticity of the oligodendrocyte lineage, even in the adult with a certain potentiality for myelin repair after experimental demyelination or human diseases.

scholarly journals Identification of the first small-molecule ligand of the neuronal receptor sortilin and structure determination of the receptor–ligand complex

2014 ◽  
Vol 70 (2) ◽  
pp. 451-460 ◽  
Author(s):  
Jacob Lauwring Andersen ◽  
Tenna Juul Schrøder ◽  
Søren Christensen ◽  
Dorthe Strandbygård ◽  
Lone Tjener Pallesen ◽  
...  
Keyword(s):  
Small Molecule ◽  
Binding Mode ◽  
Membrane Glycoprotein ◽  
Type I ◽  
Ligand Complex ◽  
Neuronal Viability ◽  
The Central Nervous System ◽  
Vacuolar Protein ◽  
Small Molecule Ligand

Sortilin is a type I membrane glycoprotein belonging to the vacuolar protein sorting 10 protein (Vps10p) family of sorting receptors and is most abundantly expressed in the central nervous system. Sortilin has emerged as a key player in the regulation of neuronal viability and has been implicated as a possible therapeutic target in a range of disorders. Here, the identification of AF40431, the first reported small-molecule ligand of sortilin, is reported. Crystals of the sortilin–AF40431 complex were obtained by co-crystallization and the structure of the complex was solved to 2.7 Å resolution. AF40431 is bound in the neurotensin-binding site of sortilin, with the leucine moiety of AF40431 mimicking the binding mode of the C-terminal leucine of neurotensin and the 4-methylumbelliferone moiety of AF40431 forming π-stacking with a phenylalanine.

The myelin proteolipid DMalpha in fishes

2009 ◽  
Vol 6 (2) ◽  
pp. 109-112 ◽  
Author(s):  
Christian Brösamle
Keyword(s):  
Fish Species ◽  
Sequence Data ◽  
Point Mutations ◽  
Proteolipid Protein ◽  
Scaffolding Protein ◽  
Extant Species ◽  
Actinopterygian Fishes ◽  
The Central Nervous System ◽  
Pelizaeus Merzbacher Disease ◽  
Myelin Proteolipid

Vertebrate myelin membranes are compacted and held in close apposition by three structural proteins of myelin, myelin basic protein, myelin protein zero (MPZ) and myelin proteolipid protein (PLP1/DMalpha). PLP1/DMalpha is considered to function as a scaffolding protein and play a role in intracellular trafficking in oligodendrocytes. In humans, point mutations, duplications or deletions of PLP1 are associated with Pelizaeus–Merzbacher disease and spastic paraplegia Type 2. PLP1 is highly conserved between mammals, but less so in lower vertebrates. This has led some researchers to question whether certain fish species express PLP1 orthologues at all, and to suggest that the function of PLP1/DMalpha in the central nervous system (CNS) may have been taken over by MPZ. Here, we review the evidence for the conservation of orthologues of PLP1/DMalpha in actinopterygian fishes and provide a comparison of currently available sequence data across 17 fish species. Our analysis demonstrates that orthologues of PLP1/DMalpha have been retained and are functionally expressed in many, if not all, extant species of bony fish. Many of the amino acids that, when mutated, are associated with severe CNS pathology are conserved in teleosts, demonstrating conservation of essential functions and justifying the development of novel disease models in species such as the zebrafish.

scholarly journals Effects of Ginkgo biloba on Early Decompression after Spinal Cord Injury

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Xing Guo ◽  
Xiaotie Wang ◽  
Jin Dong ◽  
Wei Lv ◽  
Shandou Zhao ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Ginkgo Biloba ◽  
Antioxidant Properties ◽  
Severe Trauma ◽  
Cellular Damage ◽  
Pathological Mechanism ◽  
Cord Injury ◽  
The Central Nervous System

Spinal cord injury (SCI) is a severe trauma of the central nervous system characterized by high disability and high mortality. Clinical progress has been achieved in understanding the pathological mechanism of SCI and its early treatment, but the results are unsatisfactory. In China, increasing attention has been paid to the role of traditional Chinese medicine in the treatment of SCI. In particular, extracts from the leaves of Ginkgo biloba (maidenhair tree), which have been reported to exert anti-inflammatory and antioxidant properties and repair a variety of active cellular damage, have been applied therapeutically for centuries. In this study, we established a rat SCI model to investigate the effects of Ginkgo biloba leaves on decompression at different stages of SCI. The application of Ginkgo biloba leaves during the decompression of SCI at different time points, the neurological recovery of SCI, and the underlying molecular mechanism were explored. The findings provide reliable experimental data that reveal the mechanism of GBI (Ginkgo biloba injection) in the clinical treatment of SCI.

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