scholarly journals Direct uptake mechanism in lysosome required for neuromuscular homeostasis

2020 ◽  
Author(s):  
Yuuki Fujiwara ◽  
Viorica Raluca Contu ◽  
Chihana Kabuta ◽  
Megumu Ogawa ◽  
Hiromi Fujita ◽  
...  
Keyword(s):  
Dominant Negative ◽  
Loss Of Function ◽  
Lysosomal Degradation ◽  
Uptake Mechanism ◽  
Cytoplasmic Inclusions ◽  
Cytosolic Proteins ◽  
Vacuolar Myopathy ◽  
Wide Range ◽  
Cellular Components ◽  
Rimmed Vacuolar Myopathy

Regulated degradation of cellular components plays an essential role in homeostasis. Accumulating evidence indicates the importance of lysosomal degradation of cellular proteins1: Dysfunctions in multiple pathways to deliver cytosolic substrates into lysosomes are related to various diseases, including cancers, neurodegenerative diseases, and myopathies2. However, much of the effort at understanding such pathways has been devoted to studies on macroautophagy, which entails vast and dynamic rearrangement of membrane structure, and knowledge on other delivery systems and functions of lysosomes per se remains scant. Here, we show that cytosolic proteins are directly imported into lysosomes by a mechanism distinct from any known pathways and degraded. We find that a lysosomal membrane protein, SIDT2, which was previously reported as a putative nucleic acid transporter, is involved in the translocation of substrate proteins in this system. Gain- and loss-of-function analyses reveal that SIDT2 contributes conspicuously to the lysosomal degradation of a wide range of cytosolic proteins in cells at the constitutive level. Furthermore, a dominant-negative type of mutation in SIDT2 causes familial rimmed vacuolar myopathy in humans. Sidt2 knockout mice recapitulated typical features of rimmed vacuolar myopathy, including atrophy and accumulation of cytoplasmic inclusions in skeletal muscles. These results reveal a previously unknown pathway of proteolysis in lysosomes and highlight the importance of noncanonical types of autophagy in human physiology and pathophysiology.

scholarly journals Mini-Review Regarding the Applicability of Genome Editing Techniques Developed for Studying Infertility

Diagnostics ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 246
Author(s):  
Bogdan Doroftei ◽  
Ovidiu-Dumitru Ilie ◽  
Maria Puiu ◽  
Alin Ciobica ◽  
Ciprian Ilea
Keyword(s):  
Motor Activity ◽  
Experimental Model ◽  
Zinc Finger ◽  
Biomedical Research ◽  
Zinc Finger Nucleases ◽  
Loss Of Function ◽  
Transcription Activator ◽  
Phenotypic Changes ◽  
Wide Range ◽  
Short Palindromic Repeat

Infertility is a highly debated topic today. It has been long hypothesized that infertility has an idiopathic cause, but recent studies demonstrated the existence of a genetic substrate. Fortunately, the methods of editing the human genome proven to be revolutionary. Following research conducted, we identified a total of 21 relevant studies; 14 were performed on mice, 5 on zebrafish and 2 on rats. We concluded that over forty-four genes in total are dispensable for fertility in both sexes without affecting host homeostasis. However, there are genes whose loss-of-function induces moderate to severe phenotypic changes in both sexes. There were situations in which the authors reported infertility, exhibited by the experimental model, or other pathologies such as cryptorchidism, cataracts, or reduced motor activity. Overall, zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 are techniques that offer a wide range of possibilities for studying infertility, even to create mutant variants. It can be concluded that ZFNs, TALENs, and CRISPR/Cas9 are crucial tools in biomedical research.

scholarly journals Hematopoietic Stem Cell Transplantation Resolves the Immune Deficit Associated with STAT3-Dominant-Negative Hyper-IgE Syndrome

2021 ◽  
Author(s):  
Stephanie C. Harrison ◽  
Christo Tsilifis ◽  
Mary A. Slatter ◽  
Zohreh Nademi ◽  
Austen Worth ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Early Report ◽  
Dominant Negative ◽  
Loss Of Function ◽  
Hematopoietic Stem ◽  
Hyper Ige Syndrome

AbstractAutosomal dominant hyper-IgE syndrome caused by dominant-negative loss-of-function mutations in signal transducer and activator of transcription factor 3 (STAT3) (STAT3-HIES) is a rare primary immunodeficiency with multisystem pathology. The quality of life in patients with STAT3-HIES is determined by not only the progressive, life-limiting pulmonary disease, but also significant skin disease including recurrent infections and abscesses requiring surgery. Our early report indicated that hematopoietic stem cell transplantation might not be effective in patients with STAT3-HIES, although a few subsequent reports have reported successful outcomes. We update on progress of our patient now with over 18 years of follow-up and report on an additional seven cases, all of whom have survived despite demonstrating significant disease-related pathology prior to transplant. We conclude that effective cure of the immunological aspects of the disease and stabilization of even severe lung involvement may be achieved by allogeneic hematopoietic stem cell transplantation. Recurrent skin infections and abscesses may be abolished. Donor TH17 cells may produce comparable levels of IL17A to healthy controls. The future challenge will be to determine which patients should best be offered this treatment and at what point in their disease history.

P2.26 Clinical, histological and molecular genetic features of a congenital severe infantile rimmed vacuolar myopathy

2010 ◽  
Vol 20 (9-10) ◽  
pp. 626
Author(s):  
A. D’Amico ◽  
S. Petrini ◽  
F. Fattori ◽  
M. Verardo ◽  
R. Boldrini ◽  
...  
Keyword(s):  
Molecular Genetic ◽  
Vacuolar Myopathy ◽  
Genetic Features ◽  
Rimmed Vacuolar Myopathy

scholarly journals A Modified Screening System for Loss-of-Function and Dominant Negative Alleles of Essential MCMV Genes

PLoS ONE ◽  
2014 ◽  
Vol 9 (4) ◽  
pp. e94918
Author(s):  
Madlen Pogoda ◽  
Jens B. Bosse ◽  
Karl-Klaus Conzelmann ◽  
Ulrich H. Koszinowski ◽  
Zsolt Ruzsics
Keyword(s):  
Dominant Negative ◽  
Screening System ◽  
Loss Of Function

Implementation of Shape Memory Alloys as Active Elements in Injuries Recuperative Equipment

2014 ◽  
Vol 657 ◽  
pp. 392-396
Author(s):  
Adela Ursanu Dragoş ◽  
Sergiu Stanciu ◽  
Nicanor Cimpoeşu ◽  
Mihai Dumitru ◽  
Ciprian Paraschiv
Keyword(s):  
Shape Memory Alloys ◽  
Shape Memory ◽  
Spinal Cord Injuries ◽  
Good Alternative ◽  
Careful Consideration ◽  
Damping Capacity ◽  
Loss Of Function ◽  
User Friendliness ◽  
Wide Range ◽  
Constructive Models

Entire or partial loss of function in the shoulder, elbow or wrist represent an increasingly common ailment connected to a wide range of injuries or other conditions including sports, occupational, spinal cord injuries or strokes. A general treatment of these problems relies on physiotherapy procedures. An increasing number of metallic materials are continuously being developed to expect the requirements for different engineering applications including biomedical field. Few constructive models that can involve intelligent materials are analyzed to establish the advantages in usage of shape memory elements mechanical implementation. The shape memory effect, superelasticity and damping capacity are unique characteristics at metallic alloys which demand careful consideration in both design and manufacturing processes. The actual rehabilitation systems can be improved using smart elements in motorized equipments like robotic systems. Shape memory alloys, especially NiTi (nitinol), represent a very good alternative for actuation in equipments with moving dispositive based on very good actuation properties, low mass, small size, safety and user friendliness. In this article the actuation and the force characteristics were analyzed to investigate a relationship between the bending angle and the actuation real value.

Zinc Regulation in the Lobster Homarus Gammarus: Importance of Different Pathways of Absorption and Excretion

1986 ◽  
Vol 66 (1) ◽  
pp. 175-199 ◽  
Author(s):  
G. W. Bryan ◽  
L. G. Hummerstone ◽  
Eileen Ward
Keyword(s):  
Sea Water ◽  
Carcinus Maenas ◽  
The Body ◽  
Shore Crab ◽  
Freshwater Crayfish ◽  
Uptake Mechanism ◽  
Major Pathway ◽  
Homarus Gammarus ◽  
Wide Range ◽  
Body Concentration

Zinc is one of the most important of the essential trace metals and more than 90 zinc-containing enymes and proteins have been discovered: furthermore, zinc increases the activity of many other enzymes (Vallee, 1978). It is not surprising, therefore, that in some groups of animals the body concentration is regulated against fluctuations in intake. Decapod crustaceans comprise one such group, although the ways in which regulation is achieved vary from species to species. In the freshwater crayfish, Austropotamobius pallipes, excretion in the faeces is a major pathway for removing zinc (Bryan, 1967a) whereas in the shore crab Carcinus maenas losses over the body surface also assume considerable importance (Bryan, 1966). On the other hand, preliminary work on the lobster Homarus gammarus (formerly H. vulgaris) suggests that in this species urinary excretion plays a major role in regulation (Bryan, 1964). The present work continues the study of zinc regulation in lobsters and its main aims are: (1) to measure rates of absorption from sea water over a wide range of concentrations and study the uptake mechanism; (2) to examine absorption from the stomach under different conditions; (3) to determine the relative importance of different pathways for the removal of zinc in response to various levels of intake.

scholarly journals Early Events during BK Virus Entry and Disassembly

2008 ◽  
Vol 83 (3) ◽  
pp. 1350-1358 ◽  
Author(s):  
Mengxi Jiang ◽  
Johanna R. Abend ◽  
Billy Tsai ◽  
Michael J. Imperiale
Keyword(s):  
Bk Virus ◽  
Dominant Negative ◽  
Host Cells ◽  
Human Polyomavirus ◽  
Microtubule Network ◽  
Early Entry ◽  
Dominant Negative Form ◽  
Immunosuppressed Patients ◽  
Capsid Protein Vp1 ◽  
Cellular Components

ABSTRACT BK virus (BKV) is a nonenveloped, ubiquitous human polyomavirus that establishes a persistent infection in healthy individuals. It can be reactivated, however, in immunosuppressed patients and cause severe diseases, including polyomavirus nephropathy. The entry and disassembly mechanisms of BKV are not well defined. In this report, we characterized several early events during BKV infection in primary human renal proximal tubule epithelial (RPTE) cells, which are natural host cells for BKV. Our results demonstrate that BKV infection in RPTE cells involves an acidic environment relatively early during entry, followed by transport along the microtubule network to reach the endoplasmic reticulum (ER). A distinct disulfide bond isomerization and cleavage pattern of the major capsid protein VP1 was observed, which was also influenced by alterations in pH and disruption of trafficking to the ER. A dominant negative form of Derlin-1, an ER protein required for retro-translocation of certain misfolded proteins, inhibited BKV infection. Consistent with this, we detected an interaction between Derlin-1 and VP1. Finally, we show that proteasome function is also linked to BKV infection and capsid rearrangement. These results indicate that BKV early entry and disassembly are highly regulated processes involving multiple cellular components.

scholarly journals Ultrabithorax Is a Micromanager of Hindwing Identity in Butterflies and Moths

2021 ◽  
Vol 9 ◽  
Author(s):  
Amruta Tendolkar ◽  
Aaron F. Pomerantz ◽  
Christa Heryanto ◽  
Paul D. Shirk ◽  
Nipam H. Patel ◽  
...  
Keyword(s):  
Regulatory Networks ◽  
Targeted Mutagenesis ◽  
Junonia Coenia ◽  
Wing Venation ◽  
Loss Of Function ◽  
Color Patterns ◽  
Wide Range ◽  
Range Of Functions ◽  
Gene Regulatory ◽  
Pyralid Moth

The forewings and hindwings of butterflies and moths (Lepidoptera) are differentiated from each other, with segment-specific morphologies and color patterns that mediate a wide range of functions in flight, signaling, and protection. The Hox gene Ultrabithorax (Ubx) is a master selector gene that differentiates metathoracic from mesothoracic identities across winged insects, and previous work has shown this role extends to at least some of the color patterns from the butterfly hindwing. Here we used CRISPR targeted mutagenesis to generate Ubx loss-of-function somatic mutations in two nymphalid butterflies (Junonia coenia, Vanessa cardui) and a pyralid moth (Plodia interpunctella). The resulting mosaic clones yielded hindwing-to-forewing transformations, showing Ubx is necessary for specifying many aspects of hindwing-specific identities, including scale morphologies, color patterns, and wing venation and structure. These homeotic phenotypes showed cell-autonomous, sharp transitions between mutant and non-mutant scales, except for clones that encroached into the border ocelli (eyespots) and resulted in composite and non-autonomous effects on eyespot ring determination. In the pyralid moth, homeotic clones converted the folding and depigmented hindwing into rigid and pigmented composites, affected the wing-coupling frenulum, and induced ectopic scent-scales in male androconia. These data confirm Ubx is a master selector of lepidopteran hindwing identity and suggest it acts on many gene regulatory networks involved in wing development and patterning.

scholarly journals Rett-causing mutations reveal two domains critical for MeCP2 function and for toxicity in MECP2 duplication syndrome mice

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Laura Dean Heckman ◽  
Maria H Chahrour ◽  
Huda Y Zoghbi
Keyword(s):  
Transcriptional Repression ◽  
Neurological Disorder ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Loss Of Function ◽  
Gene Encoding ◽  
C Terminus ◽  
Mecp2 Duplication Syndrome ◽  
Negative Effect ◽  
Duplication Syndrome

Loss of function of the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2) causes the progressive neurological disorder Rett syndrome (RTT). Conversely, duplication or triplication of Xq28 causes an equally wide-ranging progressive neurological disorder, MECP2 duplication syndrome, whose features overlap somewhat with RTT. To understand which MeCP2 functions cause toxicity in the duplication syndrome, we generated mouse models expressing endogenous Mecp2 along with a RTT-causing mutation in either the methyl-CpG binding domain (MBD) or the transcriptional repression domain (TRD). We determined that both the MBD and TRD must function for doubling MeCP2 to be toxic. Mutating the MBD reproduces the null phenotype and expressing the TRD mutant produces milder RTT phenotypes, yet both mutations are harmless when expressed with endogenous Mecp2. Surprisingly, mutating the TRD is more detrimental than deleting the entire C-terminus, indicating a dominant-negative effect on MeCP2 function, likely due to the disruption of a basic cluster.

Cation channel regulation by COOH-terminal cytoplasmic tail of polycystin-1: mutational and functional analysis

2002 ◽  
Vol 8 (2) ◽  
pp. 87-98 ◽  
Author(s):  
David H. Vandorpe ◽  
Sabine Wilhelm ◽  
Lianwei Jiang ◽  
Oxana Ibraghimov-Beskrovnaya ◽  
Marina N. Chernova ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Point Mutations ◽  
Coiled Coil ◽  
Cytoplasmic Tail ◽  
Surface Expression ◽  
Dominant Negative ◽  
Cation Channel ◽  
Loss Of Function ◽  
Cation Current ◽  
Autosomal Dominant Polycystic Kidney

Polycystin-1 (PKD1) mutations account for ∼85% of autosomal dominant polycystic kidney disease (ADPKD). We have shown previously that oocyte surface expression of a transmembrane fusion protein encoding part of the cytoplasmic COOH terminus of PKD1 increases activity of a Ca2+-permeable cation channel. We show here that human ADPKD mutations incorporated into this fusion protein attenuated or abolished encoded cation currents. Point mutations and truncations showed that cation current expression requires integrity of a region encompassing the putative coiled coil domain of the PKD1 cytoplasmic tail. Whereas these loss-of-function mutants did not exhibit dominant negative phenotypes, coexpression of a fusion protein expressing the interacting COOH-terminal cytoplasmic tail of PKD2 did suppress cation current. Liganding of the ectodomain of the PKD1 fusion protein moderately activated cation current. The divalent cation permeability and pharmacological profile of the current has been extended. Inducible expression of the PKD1 fusion in EcR-293 cells was also associated with activation of cation channels and increased Ca2+ entry.

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