Sortilin: a new player in dementia and Alzheimer-type neuropathology

2018 ◽  
Vol 96 (5) ◽  
pp. 491-497 ◽  
Author(s):  
Shu-Yin Xu ◽  
Juan Jiang ◽  
Aihua Pan ◽  
Cai Yan ◽  
Xiao-Xin Yan
Keyword(s):  
Protein Sorting ◽  
Critical Role ◽  
Animal Experiments ◽  
Amyloid Plaque ◽  
Mortality Factor ◽  
Human Populations ◽  
The Past ◽  
Age Related ◽  
Intracellular Compartments ◽  
Vacuolar Protein

Age-related dementias are now a major mortality factor among most human populations in the world, with Alzheimer’s disease (AD) being the leading dementia-causing neurodegenerative disease. The pathogenic mechanism underlying dementia disorders, and AD in particular, remained largely unknown. Efforts to develop drugs targeting the disease’s hallmark lesions, such as amyloid plaque and tangle pathologies, have been unsuccessful so far. The vacuolar protein sorting 10p (Vps10p) family plays a critical role in membrane signal transduction and protein sorting and trafficking between intracellular compartments. Data emerging during the past few years point to an involvement of this family in the development of AD. Specifically, the Vps10p member sortilin has been shown to participate in amyloid plaque formation, tau phosphorylation, abnormal protein sorting and apoptosis. In this minireview, we update some latest findings from animal experiments and human brain studies suggesting that abnormal sortilin expression is associated with AD-type neuropathology, warranting further research that might lead to novel targets for the development of AD therapies.

scholarly journals A Critical Role for Toxoplasma gondii Vacuolar Protein Sorting VPS9 in Secretory Organelle Biogenesis and Host Infection

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Takaya Sakura ◽  
Fabien Sindikubwabo ◽  
Lena K. Oesterlin ◽  
Hugo Bousquet ◽  
Christian Slomianny ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Protein Sorting ◽  
Critical Role ◽  
Organelle Biogenesis ◽  
Vacuolar Protein Sorting ◽  
Host Infection ◽  
Vacuolar Protein

scholarly journals Acidification of the lysosome-like vacuole and the vacuolar H+-ATPase are deficient in two yeast mutants that fail to sort vacuolar proteins.

1989 ◽  
Vol 109 (1) ◽  
pp. 93-100 ◽  
Author(s):  
J H Rothman ◽  
C T Yamashiro ◽  
C K Raymond ◽  
P M Kane ◽  
T H Stevens
Keyword(s):  
Protein Sorting ◽  
Critical Role ◽  
Normal Function ◽  
Yeast Cells ◽  
Zymogen Activation ◽  
Animal Cells ◽  
Vacuolar Acidification ◽  
Vacuolar Protein ◽  
Vacuolar Membranes ◽  
Yeast Mutants

Organelle acidification plays a demonstrable role in intracellular protein processing, transport, and sorting in animal cells. We investigated the relationship between acidification and protein sorting in yeast by treating yeast cells with ammonium chloride and found that this lysosomotropic agent caused the mislocalization of a substantial fraction of the newly synthesized vacuolar (lysosomal) enzyme proteinase A (PrA) to the cell surface. We have also determined that a subset of the vpl mutants, which are deficient in sorting of vacuolar proteins (Rothman, J. H., and T. H. Stevens. 1986. Cell. 47:1041-1051; Rothman, J. H., I. Howald, and T. H. Stevens. EMBO [Eur. Mol. Biol. Organ.] J. In press), failed to accumulate the lysosomotropic fluorescent dye quinacrine within their vacuoles, mimicking the phenotype of wild-type cells treated with ammonium. The acidification defect of vpl3 and vpl6 mutants correlated with a marked deficiency in vacuolar ATPase activity, diminished levels of two immunoreactive subunits of the protontranslocating ATPase (H+-ATPase) in purified vacuolar membranes, and accumulation of the intracellular portion of PrA as the precursor species. Therefore, some of the VPL genes are required for the normal function of the yeast vacuolar H+-ATPase complex and may encode either subunits of the enzyme or components required for its assembly and targeting. Collectively, these findings implicate a critical role for acidification in vacuolar protein sorting and zymogen activation in yeast, and suggest that components of the yeast vacuolar acidification system may be identified by examining mutants defective in sorting of vacuolar proteins.

Basic Studies of Various 99mTc-Labelled Renal Agents and Clinical Application of 99mTc-Malate

1977 ◽  
Vol 16 (01) ◽  
pp. 36-41 ◽  
Author(s):  
T. Machida ◽  
M. Miki ◽  
M. Ueda ◽  
A. Tanaka ◽  
I. Ikeda
Keyword(s):  
Excretion Rate ◽  
Animal Experiments ◽  
Imaging Agents ◽  
Half Time ◽  
Clinical Experiences ◽  
Labelling Efficiency ◽  
Urinary Excretion Rate ◽  
Renal Imaging ◽  
The Past ◽  
Basic Studies

SummaryVarious renal imaging agents that were reported in the past and a new agent, 99mTc-malate as well as 99mTc-cystein acetazolamide complex were prepared using electrolysis and electrochemical methods. These were studied for their labelling efficiency. After animal experiments with selected 99mTc-com- pounds, 99mTc-rnalate proved to be sufficient for renal imaging with adequate concentration. 99mTcmalate differs from other renal imaging agents in the utilization of endogeneous metabolic product.The first half time of 99mTc-malate in humans is 17 minutes, on the average, and the urinary excretion rate of 99mTc-malate is 36±6.05% in 1 hour after intravenous administration, 44 ± 3.41% in 2 hours and 50 + 5.62% in 3 hours.In our 40 clinical experiences of 99m-Tc-rnalate, most cases demonstrated quite clear renal images in the serial scintiphotos except cases whose serum creatinines were over 4.5 mg/dl.

The Important Roles of Matrix Metalloproteinases in the Pathophysiology of Obesity

2017 ◽  
Vol 68 (7) ◽  
pp. 1481-1484 ◽  
Author(s):  
Radu Mihail Mirica ◽  
Mihai Ionescu ◽  
Alexandra Mirica ◽  
Octav Ginghina ◽  
Razvan Iosifescu ◽  
...  
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Matrix Metalloproteinases ◽  
English Language ◽  
Critical Role ◽  
Animal Experiments ◽  
Hdl Cholesterol ◽  
Tissue Growth ◽  
Basement Membranes ◽  
Body Weight Reduction

Obesity involves the growth of adipose tissue cells (adipocytes and preadipocytes), as well as microvascular endothelial cells. Matrix metalloproteinases (MMPs) are relevant ezymes for the modulation of extracellular matrix (ECM) and adipocyte and preadipocytes differentiation. They are elevated in obese patients, generating abnormal ECM metabolism.[1]. This article proposes a thorough study of literature with focus on the important roles of matrix metalloproteinases in the pathophysiology of obesity. The article represents a narrative review based on an English-language PubMed research of the medical literature regardind important aspects of the proposed aim. MMP-2 activity was signi�cantly higher than MMP-9, both activities were detectable. MMP-9 was strongly correlated with body weight parameters before surgery, as well as after significant body weight reduction as a result of bariatric surgery. Concerning MMP-2 and MMP-9 they are also involved in the turnover of basement membranes both those of adipose tissue and endothelial. MMP-9 levels were moderately correlated with HDL cholesterol levels. Taken together, the present data suggest that changes in ECM through MMP-mediated degradation might play a critical role in the adipocyte differentiation process. These findings are detected both in clinical trials and in laboratory animal experiments. It is then tempting to speculate that the adipocyte-derived MMPs might represent a new pharmacological target for the inhibition of adipose tissue growth by inhibiting adipose differentiation as well as angiogenic process.

The Role of Glyoxalase in Glycation and Carbonyl Stress Induced Metabolic Disorders

2020 ◽  
Vol 21 (9) ◽  
pp. 846-859
Author(s):  
Mohd Saeed ◽  
Mohd Adnan Kausar ◽  
Rajeev Singh ◽  
Arif J. Siddiqui ◽  
Asma Akhter
Keyword(s):  
Protein Misfolding ◽  
Covalent Binding ◽  
Critical Role ◽  
Enzymatic Reaction ◽  
Treatment Strategies ◽  
Bioactive Molecules ◽  
Carbonyl Stress ◽  
Defense System ◽  
Pathological Conditions ◽  
Age Related

Glycation refers to the covalent binding of sugar molecules to macromolecules, such as DNA, proteins, and lipids in a non-enzymatic reaction, resulting in the formation of irreversibly bound products known as advanced glycation end products (AGEs). AGEs are synthesized in high amounts both in pathological conditions, such as diabetes and under physiological conditions resulting in aging. The body’s anti-glycation defense mechanisms play a critical role in removing glycated products. However, if this defense system fails, AGEs start accumulating, which results in pathological conditions. Studies have been shown that increased accumulation of AGEs acts as key mediators in multiple diseases, such as diabetes, obesity, arthritis, cancer, atherosclerosis, decreased skin elasticity, male erectile dysfunction, pulmonary fibrosis, aging, and Alzheimer’s disease. Furthermore, glycation of nucleotides, proteins, and phospholipids by α-oxoaldehyde metabolites, such as glyoxal (GO) and methylglyoxal (MGO), causes potential damage to the genome, proteome, and lipidome. Glyoxalase-1 (GLO-1) acts as a part of the anti-glycation defense system by carrying out detoxification of GO and MGO. It has been demonstrated that GLO-1 protects dicarbonyl modifications of the proteome and lipidome, thereby impeding the cell signaling and affecting age-related diseases. Its relationship with detoxification and anti-glycation defense is well established. Glycation of proteins by MGO and GO results in protein misfolding, thereby affecting their structure and function. These findings provide evidence for the rationale that the functional modulation of the GLO pathway could be used as a potential therapeutic target. In the present review, we summarized the newly emerged literature on the GLO pathway, including enzymes regulating the process. In addition, we described small bioactive molecules with the potential to modulate the GLO pathway, thereby providing a basis for the development of new treatment strategies against age-related complications.

Molecular Mechanisms of Complement System Proteins and Matrix Metalloproteinases in the Pathogenesis of Age-Related Macular Degeneration

2019 ◽  
Vol 19 (10) ◽  
pp. 705-718 ◽  
Author(s):  
Naima Mansoor ◽  
Fazli Wahid ◽  
Maleeha Azam ◽  
Khadim Shah ◽  
Anneke I. den Hollander ◽  
...  
Keyword(s):  
Matrix Metalloproteinases ◽  
Macular Degeneration ◽  
Complement System ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Age Related Macular Degeneration ◽  
Genetic Changes ◽  
Complement System Proteins ◽  
Age Related ◽  
Common Genetic Variants

: Age-related macular degeneration (AMD) is an eye disorder affecting predominantly the older people above the age of 50 years in which the macular region of the retina deteriorates, resulting in the loss of central vision. The key factors associated with the pathogenesis of AMD are age, smoking, dietary, and genetic risk factors. There are few associated and plausible genes involved in AMD pathogenesis. Common genetic variants (with a minor allele frequency of >5% in the population) near the complement genes explain 40–60% of the heritability of AMD. The complement system is a group of proteins that work together to destroy foreign invaders, trigger inflammation, and remove debris from cells and tissues. Genetic changes in and around several complement system genes, including the CFH, contribute to the formation of drusen and progression of AMD. Similarly, Matrix metalloproteinases (MMPs) that are normally involved in tissue remodeling also play a critical role in the pathogenesis of AMD. MMPs are involved in the degradation of cell debris and lipid deposits beneath retina but with age their functions get affected and result in the drusen formation, succeeding to macular degeneration. In this review, AMD pathology, existing knowledge about the normal and pathological role of complement system proteins and MMPs in the eye is reviewed. The scattered data of complement system proteins, MMPs, drusenogenesis, and lipofusogenesis have been gathered and discussed in detail. This might add new dimensions to the understanding of molecular mechanisms of AMD pathophysiology and might help in finding new therapeutic options for AMD.

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.

scholarly journals Small Molecule Inhibitors of Influenza Virus Entry

2021 ◽  
Vol 14 (6) ◽  
pp. 587
Author(s):  
Zhaoyu Chen ◽  
Qinghua Cui ◽  
Michael Caffrey ◽  
Lijun Rong ◽  
Ruikun Du
Keyword(s):  
Influenza Virus ◽  
Membrane Fusion ◽  
Small Molecule ◽  
Drug Target ◽  
Small Molecule Inhibitors ◽  
Virus Entry ◽  
Critical Role ◽  
Structural Basis ◽  
Future Directions ◽  
The Past

Hemagglutinin (HA) plays a critical role during influenza virus receptor binding and subsequent membrane fusion process, thus HA has become a promising drug target. For the past several decades, we and other researchers have discovered a series of HA inhibitors mainly targeting its fusion machinery. In this review, we summarize the advances in HA-targeted development of small molecule inhibitors. Moreover, we discuss the structural basis and mode of action of these inhibitors, and speculate upon future directions toward more potent inhibitors of membrane fusion and potential anti-influenza drugs.

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