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https://www.readbyqxmd.com/read/28934392/nceh-1-modulates-cholesterol-metabolism-and-protects-against-%C3%AE-synuclein-toxicity-in-a-c-elegans-model-of-parkinson-s-disease
#1
Siyuan Zhang, Samantha A Glukhova, Kim A Caldwell, Guy A Caldwell
Parkinson's disease (PD) is an aging-associated neurodegenerative disease affecting millions worldwide. Misfolding, oligomerization and accumulation of the human α-synuclein protein is a key pathological hallmark of PD and is associated with the progressive loss of dopaminergic neurons over the course of aging. Lifespan extension via the suppression of IGF-1/insulin-like signaling (IIS) offers a possibility to retard disease onset through induction of metabolic changes that provide neuroprotection. The nceh-1 gene of Caenorhabditis elegans encodes an ortholog of neutral cholesterol ester hydrolase 1 (NCEH-1), an IIS downstream protein that was identified in a screen as a modulator of α-synuclein accumulation in vivo...
October 1, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28929194/adapting-secretory-proteostasis-and-function-through-the-unfolded-protein-response
#2
Madeline Y Wong, Andrew S DiChiara, Patreece H Suen, Kenny Chen, Ngoc-Duc Doan, Matthew D Shoulders
Cells address challenges to protein folding in the secretory pathway by engaging endoplasmic reticulum (ER)-localized protective mechanisms that are collectively termed the unfolded protein response (UPR). By the action of the transmembrane signal transducers IRE1, PERK, and ATF6, the UPR induces networks of genes whose products alleviate the burden of protein misfolding. The UPR also plays instructive roles in cell differentiation and development, aids in the response to pathogens, and coordinates the output of professional secretory cells...
September 20, 2017: Current Topics in Microbiology and Immunology
https://www.readbyqxmd.com/read/28928748/a-peptide-fc-opsonin-with-pan-amyloid-reactivity
#3
James S Foster, Angela D Williams, Sallie Macy, Tina Richey, Alan Stuckey, Daniel Craig Wooliver, Richa Koul-Tiwari, Emily B Martin, Stephen J Kennel, Jonathan S Wall
There is a continuing need for therapeutic interventions for patients with the protein misfolding disorders that result in systemic amyloidosis. Recently, specific antibodies have been employed to treat AL amyloidosis by opsonizing tissue amyloid deposits thereby inducing cell-mediated dissolution and organ improvement. To develop a pan-amyloid therapeutic agent, we have produced an Fc-fusion product incorporating a peptide, p5, which binds many if not all forms of amyloid. This protein, designated Fcp5, expressed in mammalian cells, forms the desired bivalent dimer structure and retains pan-amyloid reactivity similar to the p5 peptide as measured by immunosorbent assays, immunohistochemistry, surface plasmon resonance, and pulldown assays using radioiodinated Fcp5...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28927525/alpha-1-antitrypsin-deficiency-genetic-variations-clinical-manifestations-and-therapeutic-interventions
#4
REVIEW
Younis Mohammad Hazari, Arif Bashir, Mudasir Habib, Samirul Bashir, Huma Habib, M Abul Qasim, Naveed Nazir Shah, Ehtishamul Haq, Jeffrey Teckman, Khalid Majid Fazili
Alpha-1-antitrypsin (AAT) is an acute phase secretory glycoprotein that inhibits neutrophil proteases like elastase and is considered as the archetype of a family of structurally related serine-protease inhibitors termed serpins. Serum AAT predominantly originates from liver and increases three to five fold during host response to tissue injury and inflammation. The AAT deficiency is unique among the protein-misfolding diseases in that it causes target organ injury by both loss-of-function and gain-of-toxic function mechanisms...
July 2017: Mutation Research
https://www.readbyqxmd.com/read/28924012/inhibition-of-il-1%C3%AE-signaling-normalizes-nmda-dependent-neurotransmission-and-reduces-seizure-susceptibility-in-a-mouse-model-of-creutzfeldt-jakob-disease
#5
Ilaria Bertani, Valentina Iori, Massimo Trusel, Mattia Maroso, Claudia Foray, Susanna Mantovani, Raffaella Tonini, Annamaria Vezzani, Roberto Chiesa
Creutzfeldt-Jakob disease (CJD) is a neurodegenerative disorder caused by prion protein (PrP) misfolding, clinically recognized by cognitive and motor deficits, electroencephalographic (EEG) abnormalities and seizures. Its neurophysiological bases are not known. To assess the potential involvement of N-methyl-D-aspartate receptor (NMDAR) dysfunction, we analyzed NMDA-dependent synaptic plasticity in hippocampal slices from Tg(CJD) mice, which model a genetic form of CJD. Because PrP depletion may result in functional upregulation of NMDARs, we also analyzed PrP knockout (KO) mice...
September 18, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28923470/tripodal-lipoprotein-variants-with-c-terminal-hydrophobic-residues-allosterically-modulate-activity-of-the-degp-protease
#6
Hyojin Park, Yurie T Kim, Chulwon Choi, Seokhee Kim
DegP, a member of the highly conserved HtrA family of proteases, performs a regulated proteolysis of toxic misfolded proteins in the periplasm of Gram-negative bacteria. The allosteric switch between inactive and active conformations is a central mechanism to carefully control proteolytic activity of DegP and to maintain the optimal cellular fitness, but few other molecules than substrates are known to allosterically control DegP activity. Here, we demonstrate that a mutant variant of an outer membrane lipoprotein, Lpp(+Leu), can function as a novel allosteric effector that changes the dynamic range of DegP activity...
September 15, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28923065/the-heat-shock-response-in-neurons-and-astroglia-and-its-role-in-neurodegenerative-diseases
#7
REVIEW
Rebecca San Gil, Lezanne Ooi, Justin J Yerbury, Heath Ecroyd
Protein inclusions are a predominant molecular pathology found in numerous neurodegenerative diseases, including amyotrophic lateral sclerosis and Huntington's disease. Protein inclusions form in discrete areas of the brain characteristic to the type of neurodegenerative disease, and coincide with the death of neurons in that region (e.g. spinal cord motor neurons in amyotrophic lateral sclerosis). This suggests that the process of protein misfolding leading to inclusion formation is neurotoxic, and that cell-autonomous and non-cell autonomous mechanisms that maintain protein homeostasis (proteostasis) can, at times, be insufficient to prevent protein inclusion formation in the central nervous system...
September 18, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28922609/serum-proteomic-variability-associated-with-clinical-phenotype-in-familial-transthyretin-amyloidosis-attrm
#8
Gloria G Chan, Clarissa M Koch, Lawreen H Connors
Transthyretin (TTR), normally a plasma circulating protein, can become misfolded and aggregated, ultimately leading to extracellular deposition of amyloid fibrils usually targeted to heart or nerve tissues. Referred to as TTR-associated amyloidoses (ATTR), this group of diseases is frequently life threatening and fatal if untreated. ATTR, caused by amyloid-forming variant TTR proteins (ATTRm) which arise from point mutations in the TTR gene, were classically referred to as familial amyloid cardiomyopathy (FAC) or familial amyloid polyneuropathy (FAP) reflecting the clinical phenotype...
September 18, 2017: Journal of Proteome Research
https://www.readbyqxmd.com/read/28922400/protein-folding-misfolding-and-aggregation-the-importance-of-two-electron-stabilizing-interactions
#9
Andrzej Stanisław Cieplak
Proteins associated with neurodegenerative diseases are highly pleiomorphic and may adopt an all-α-helical fold in one environment, assemble into all-β-sheet or collapse into a coil in another, and rapidly polymerize in yet another one via divergent aggregation pathways that yield broad diversity of aggregates' morphology. A thorough understanding of this behaviour may be necessary to develop a treatment for Alzheimer's and related disorders. Unfortunately, our present comprehension of folding and misfolding is limited for want of a physicochemical theory of protein secondary and tertiary structure...
2017: PloS One
https://www.readbyqxmd.com/read/28922170/a-critical-assessment-of-exosomes-in-the-pathogenesis-and-stratification-of-parkinson-s-disease
#10
George K Tofaris
Extracellular vesicles including exosomes are released by a variety of cell types including neurons and exhibit molecular profiles that reflect normal and disease states. As their content represents a snapshot of the intracellular milieu, they could be exploited as biomarkers of the otherwise inaccessible brain microenvironment. In addition they may contribute to the progression of neurodegenerative disorders by facilitating the spread of misfolded proteins at distant sites or activating immune cells. This review summarizes recent advances in the study of exosomes in Parkinson's disease pathophysiology and their potential as disease biomarkers...
September 11, 2017: Journal of Parkinson's Disease
https://www.readbyqxmd.com/read/28920921/increased-intracellular-proteolysis-reduces-disease-severity-in-an-er-stress-associated-dwarfism
#11
Lorna A Mullan, Ewa J Mularczyk, Louise H Kung, Mitra Forouhan, Jordan Ma Wragg, Royston Goodacre, John F Bateman, Eileithyia Swanton, Michael D Briggs, Raymond P Boot-Handford
The short-limbed dwarfism metaphyseal chondrodysplasia type Schmid (MCDS) is linked to mutations in type X collagen, which increase ER stress by inducing misfolding of the mutant protein and subsequently disrupting hypertrophic chondrocyte differentiation. Here, we show that carbamazepine (CBZ), an autophagy-stimulating drug that is clinically approved for the treatment of seizures and bipolar disease, reduced the ER stress induced by 4 different MCDS-causing mutant forms of collagen X in human cell culture...
September 18, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28920920/er-associated-degradation-is-required-for-vasopressin-prohormone-processing-and-systemic-water-homeostasis
#12
Guojun Shi, Diane Somlo, Geun Hyang Kim, Cristina Prescianotto-Baschong, Shengyi Sun, Nicole Beuret, Qiaoming Long, Jonas Rutishauser, Peter Arvan, Martin Spiess, Ling Qi
Peptide hormones are crucial regulators of many aspects of human physiology. Mutations that alter these signaling peptides are associated with physiological imbalances that underlie diseases. However, the conformational maturation of peptide hormone precursors (prohormones) in the ER remains largely unexplored. Here, we report that conformational maturation of proAVP, the precursor for the antidiuretic hormone arginine-vasopressin, within the ER requires the ER-associated degradation (ERAD) activity of the Sel1L-Hrd1 protein complex...
September 18, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28920918/mice-deficient-for-erad-machinery-component-sel1l-develop-central-diabetes-insipidus
#13
Daniel G Bichet, Yoann Lussier
Deficiency of the antidiuretic hormone arginine vasopressin (AVP) underlies diabetes insipidus, which is characterized by the excretion of abnormally large volumes of dilute urine and persistent thirst. In this issue of the JCI, Shi et al. report that Sel1L-Hrd1 ER-associated degradation (ERAD) is responsible for the clearance of misfolded pro-arginine vasopressin (proAVP) in the ER. Additionally, mice with Sel1L deficiency, either globally or specifically within AVP-expressing neurons, developed central diabetes insipidus...
September 18, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28917050/preparation-of-selenocysteine-containing-forms-of-human-selenok-and-selenos
#14
Zhengqi Zhang, Jun Liu, Sharon Rozovsky
Selenoprotein K (SELENOK) and Selenoprotein S (SELENOS) are the members of the endoplasmic-reticulum-associated degradation (ERAD) complex, which is responsible for translocating misfolded proteins from the endoplasmic reticulum (ER) to the cytosol for degradation. Besides its involvement in the ERAD, SELENOK was shown to bind and stabilize the palmitoyl transferase DHHC6, and thus contributes to palmitoylation. SELENOK and SELENOS reside in the ER membrane by the way of a single transmembrane helix. Both contain an intrinsically disordered region with a selenocysteine (Sec) located one or two residues away from the C-terminus...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28916386/molecular-mechanisms-of-the-r61t-mutation-in-apolipoprotein-e4-a-dynamic-rescue
#15
Benfeard Williams, Marino Convertino, Jhuma Das, Nikolay V Dokholyan
The apolipoprotein E4 (ApoE4) gene is the strongest genetic risk factor for Alzheimer's disease (AD). With respect to the other common isoforms of this protein (ApoE2 and ApoE3), ApoE4 is characterized by lower stability that underlies the formation of a stable interaction between the protein's N- and C-terminal domains. AD-related cellular dysfunctions have been linked to this ApoE4 misfolded state. In this regard, it has been reported that the mutation R61T is able to rescue the deleterious cellular effects of ApoE4 by preventing the formation of the misfolded intermediate state...
September 12, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28915764/sequence-dependent-aggregation-of-peptides-and-fibril-formation
#16
Nguyen Ba Hung, Duy-Manh Le, Trinh X Hoang
Deciphering the links between amino acid sequence and amyloid fibril formation is key for understanding protein misfolding diseases. Here we use Monte Carlo simulations to study the aggregation of short peptides in a coarse-grained model with hydrophobic-polar (HP) amino acid sequences and correlated side chain orientations for hydrophobic contacts. A significant heterogeneity is observed in the aggregate structures and in the thermodynamics of aggregation for systems of different HP sequences and different numbers of peptides...
September 14, 2017: Journal of Chemical Physics
https://www.readbyqxmd.com/read/28915215/mechanisms-involved-in-secondary-cardiac-dysfunction-in-animal-models-of-trauma-and-hemorrhagic-shock
#17
Nick M Wilson, Johanna Wall, Veena Naganathar, Karim Brohi, Henry D De'Ath
Clinical evidence reveals the existence of a trauma-induced secondary cardiac injury (TISCI) that is associated with poor patient outcomes. The mechanisms leading to TISCI in injured patients are uncertain. Conversely, animal models of trauma hemorrhage have repeatedly demonstrated significant cardiac dysfunction following injury, and highlighted mechanisms through which this might occur. The aim of this review was to provide an overview of the animal studies describing TISCI and its pathophysiology.Basic science models of trauma show evidence of innate immune system activation via Toll-like receptors, the exact protagonists of which remain unclear...
October 2017: Shock
https://www.readbyqxmd.com/read/28914774/targeting-heat-shock-proteins-in-cancer-a-promising-therapeutic-approach
#18
REVIEW
Suman Chatterjee, Timothy F Burns
Heat shock proteins (HSPs) are a large family of chaperones that are involved in protein folding and maturation of a variety of "client" proteins protecting them from degradation, oxidative stress, hypoxia, and thermal stress. Hence, they are significant regulators of cellular proliferation, differentiation and strongly implicated in the molecular orchestration of cancer development and progression as many of their clients are well established oncoproteins in multiple tumor types. Interestingly, tumor cells are more HSP chaperonage-dependent than normal cells for proliferation and survival because the oncoproteins in cancer cells are often misfolded and require augmented chaperonage activity for correction...
September 15, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28913005/chaperone-based-therapies-for-disease-modification-in-parkinson-s-disease
#19
REVIEW
Erik L Friesen, Mitch L De Snoo, Luckshi Rajendran, Lorraine V Kalia, Suneil K Kalia
Parkinson's disease (PD) is the second most common neurodegenerative disorder and is characterized by the presence of pathological intracellular aggregates primarily composed of misfolded α-synuclein. This pathology implicates the molecular machinery responsible for maintaining protein homeostasis (proteostasis), including molecular chaperones, in the pathobiology of the disease. There is mounting evidence from preclinical and clinical studies that various molecular chaperones are downregulated, sequestered, depleted, or dysfunctional in PD...
2017: Parkinson's Disease
https://www.readbyqxmd.com/read/28912682/extracellular-vesicles-in-brain-tumors-and-neurodegenerative-diseases
#20
REVIEW
Federica Ciregia, Andrea Urbani, Giuseppe Palmisano
Extracellular vesicles (EVs) can be classified into apoptotic bodies, microvesicles (MVs), and exosomes, based on their origin or size. Exosomes are the smallest and best characterized vesicles which derived from the endosomal system. These vesicles are released from many different cell types including neuronal cells and their functions in the nervous system are investigated. They have been proposed as novel means for intercellular communication, which takes part not only to the normal neuronal physiology but also to the transmission of pathogenic proteins...
2017: Frontiers in Molecular Neuroscience
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