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Jade-Emmanuelle Deshaies, Lulzim Shkreta, Alexander J Moszczynski, Hadjara Sidibé, Sabrina Semmler, Aurélien Fouillen, Estelle R Bennett, Uriya Bekenstein, Laurie Destroismaisons, Johanne Toutant, Quentin Delmotte, Kathryn Volkening, Stéphanie Stabile, Anaïs Aulas, Yousra Khalfallah, Hermona Soreq, Antonio Nanci, Michael J Strong, Benoit Chabot, Christine Vande Velde
The RNA binding proteins TDP-43 (encoded by TARDBP) and hnRNP A1 (HNRNPA1) are each mutated in certain amyotrophic lateral sclerosis cases and are often mislocalized in cytoplasmic aggregates within motor neurons of affected patients. Cytoplasmic inclusions of TDP-43, which are accompanied by a depletion of nuclear TDP-43, are observed in most amyotrophic lateral sclerosis cases and nearly half of frontotemporal dementia cases. Here, we report that TDP-43 binds HNRNPA1 pre-mRNA and modulates its splicing, and that depletion of nuclear TDP-43 results in increased inclusion of a cassette exon in the HNRNPA1 transcript, and consequently elevated protein levels of an isoform containing an elongated prion-like domain, referred to as hnRNP A1B...
March 19, 2018: Brain: a Journal of Neurology
Marion Gay, Pascal Carato, Mathilde Coevoet, Nicolas Renault, Paul-Emmanuel Larchanché, Amélie Barczyk, Saïd Yous, Luc Buée, Nicolas Sergeant, Patricia Melnyk
The chloroquinoline scaffold is characteristic of anti-malarial drugs such as chloroquine (CQ) or amodiaquine (AQ). These drugs are also described for their potential effectiveness against prion disease, HCV, EBV, Ebola virus, cancer, Parkinson or Alzheimer diseases. Amyloid precursor protein (APP) metabolism is deregulated in Alzheimer's disease. Indeed, CQ modifies amyloid precursor protein (APP) metabolism by precluding the release of amyloid-beta peptides (Aβ), which accumulate in the brain of Alzheimer patients to form the so-called amyloid plaques...
March 12, 2018: Bioorganic & Medicinal Chemistry
Joanna I Loch, Piotr Bonarek, Magdalena Tworzydło, Ilona Łazińska, Joanna Szydłowska, Joanna Lipowska, Katarzyna Rzęsikowska, Krzysztof Lewiński
Chlorpromazine (CPZ) is a phenothiazine acting as dopamine antagonist. Aside from application in schizophrenia therapy, chlorpromazine is found to be a putative inhibitor of proteins involved in cancers, heritable autism disorder and prion diseases. Four new β-lactoglobulin variants with double or triple substitutions: I56F/L39A, F105L/L39A, I56F/L39A/M107F or F105L/L39A/M107F changing the shape of the binding pocket were produced and their chlorpromazine binding properties have been investigated by X-ray crystallography, circular dichroism, isothermal titration calorimetry and thermophoresis...
March 16, 2018: International Journal of Biological Macromolecules
Lu Wang, Jian Kang, Liangzhong Lim, Yuanyuan Wei, Jianxing Song
TDP-43 inclusions are characterized by a large spectrum of neurodegenerative diseases such as ALS and Alzheimer's. Functionally, TDP-43 is engaged in forming dynamic granules via liquid-liquid phase separation (LLPS), which is now recognized to be a general principle for organizing a variety of cellular membrane-less organelles. TDP-43 is composed of the N-terminal domain (NTD) adopting an ubiquitin-like fold, two RRMs and C-terminal domain (CTD) with the low-complexity (LC) prion-like sequences. Previously, only the CTD was found to undergo LLPS to form dynamic liquid droplets with relatively small numbers and sizes...
March 16, 2018: Biochemical and Biophysical Research Communications
Hanh T M Phan, Jason C Bartz, Jacob Ayers, Benoit I Giasson, Mathias Schubert, Keith B Rodenhausen, Negin Kananizadeh, Yusong Li, Shannon L Bartelt-Hunt
The assembly and accumulation of α-synuclein fibrils are implicated in the development of several neurodegenerative disorders including multiple system atrophy and Parkinson's disease. Pre-existing α-synuclein fibrils can recruit and convert soluble non-fibrillar α-synuclein to the fibrillar form similar to what is observed in prion diseases. This raises concerns regarding attachment of fibrillary α-synuclein to medical instruments and subsequent exposure of patients to α-synuclein similar to what has been observed in iatrogenic transmission of prions...
March 9, 2018: Colloids and Surfaces. B, Biointerfaces
Lulu Ning, Yuguang Mu
Prion diseases are neurodegenerative disorders characterized by the aggregation of an abnormal form of prion protein. The interaction of prion protein and cellular membrane is crucial to elucidate the occurrence and development of prion diseases. Its fragment, residues 106-126, has been proven to maintain the pathological properties of misfolded prion and was used as a model peptide. In this study, explicit solvent molecular dynamics (MD) simulations were carried out to investigate the adsorption, folding and aggregation of PrP106-126 with different sizes (2-peptides, 4-peptides and 6-peptides) on the surface of both pure neutral POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) and negatively charged POPC/POPG (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol) (3:1) lipids...
March 14, 2018: Biochimica et Biophysica Acta
Ipsita Subudhi, James Shorter
Ubiquilin 2 (UBQLN2) is an amyotrophic lateral sclerosis-linked molecular chaperone with a prion-like domain that directly engages ubiquitin to triage clients for proteasomal degradation. Dao et al. (2018) now establish that UBQLN2 forms ubiquitin-labile liquids, which may enable UBQLN2 to specifically extract ubiquitylated clients from stress granules for degradation.
March 15, 2018: Molecular Cell
Shannon N Rhoads, Zachary T Monahan, Debra S Yee, Frank P Shewmaker
Subcellular mislocalization and aggregation of the human FUS protein occurs in neurons of patients with subtypes of amyotrophic lateral sclerosis and frontotemporal dementia. FUS is one of several RNA-binding proteins that can functionally self-associate into distinct liquid-phase droplet structures. It is postulated that aberrant interactions within the dense phase-separated state can potentiate FUS's transition into solid prion-like aggregates that cause disease. FUS is post-translationally modified at numerous positions, which affect both its localization and aggregation propensity...
March 16, 2018: International Journal of Molecular Sciences
Angelica Nakagawa Lima, Ronaldo Junio de Oliveira, Antônio Sérgio Kimus Braz, Maurício Garcia de Souza Costa, David Perahia, Luis Paulo Barbour Scott
There are two different prion conformations: (1) the cellular natural (PrPC ) and (2) the scrapie (PrPSc ), an infectious form that tends to aggregate under specific conditions. PrPC and PrPSc are widely different regarding secondary and tertiary structures. PrPSc contains more and longer β-strands compared to PrPC . The lack of solved PrPSc structures precludes a proper understanding of the mechanisms related to the transition between cellular and scrapie forms, as well as the aggregation process. In order to investigate the conformational transition between PrPC and PrPSc , we applied MDeNM (molecular dynamics with excited normal modes), an enhanced sampling simulation technique that has been recently developed to probe large structural changes...
March 15, 2018: European Biophysics Journal: EBJ
Charlotte Ridler
No abstract text is available yet for this article.
March 16, 2018: Nature Reviews. Neurology
Soyoung Park, Ah-Young Oh, Jung-Hyun Cho, Min-Ho Yoon, Tae-Guen Woo, Somi Kang, Ho-Young Lee, Yunjin Jung, Bum-Joon Park
Quinacrine (QNC), anti-protozoan drug commonly used against Malaria and Giardiasis, has been recently tried for rheumatics and prion diseases via drug repositioning. In addition, several reports suggest anti-tumor effects of QNC through suppression of NF-κB and activation of p53. This study, demonstrates the anti-cancer effect of QNC via a novel pathway through the elimination of check point kinase 1/2 (Chk1/2) under p53 inactivated conditions. Inhibition of p53, by PFT-α or siRNA, promotes QNC-induced apoptosis in normal fibroblast and p53-intact cancer cells...
March 15, 2018: Molecular Cancer Research: MCR
Yeong-Min Yoo, Eui-Bae Jeung
The phenotypes of calbindin-D9k - ( CaBP-9k -) knockout (KO), calbindin - D28k - ( CaBP-28k -) KO, and CaBP-9k/28k -KO mice are similar to those of wild-type (WT) mice due to the compensatory action of other calcium transport proteins. In this study, we investigated the expression of cellular prion protein (PrPC ) in the brains of CaBP-9k -, CaBP-28k -, and CaBP-9k/28k -KO mice. PrPC expression was significantly upregulated in the brain of all three strains. Levels of phospho-Akt (Ser473) and phospho-Bad (Ser136) were significantly elevated, but those of phospho-ERK and phospho-Bad (Ser155 and 112) were significantly reduced in the brains of CaBP-9k -, CaBP-28k -, and CaBP-9k/28k -KO mice...
2018: Oxidative Medicine and Cellular Longevity
Yicai Xiao, Gaofeng Li, Yujie Chen, Yuchun Zuo, Kauthar Rashid, Tibiao He, Hua Feng, John H Zhang, Fei Liu
Iatrogenic brain injury inevitably occurs in neurosurgical operations, leading to brain edema, ischemia, intracranial hematoma, and other postoperative complications, eventually worsening neurological outcomes of patients. If apoptotic cells are not rapidly eliminated by phagocytic engulfment, they may communicate with surrounding cells to undergo secondary necrosis and releasing toxic signals. Recent studies have shown that milk fat globule-epidermal growth factor-8 (MFGE8), which promotes phagocytosis and inhibits inflammation, is an endogenous protective factor in response to brain infarction, Alzheimer's disease, subarachnoid hemorrhage, and prion disease...
2018: Frontiers in Neurology
Jatish Kumar, Hasier Eraña, Elena López-Martínez, Nathalie Claes, Víctor F Martín, Diego M Solís, Sara Bals, Aitziber L Cortajarena, Joaquín Castilla, Luis M Liz-Marzán
Amyloid fibrils, which are closely associated with various neurodegenerative diseases, are the final products in many protein aggregation pathways. The identification of fibrils at low concentration is, therefore, pivotal in disease diagnosis and development of therapeutic strategies. We report a methodology for the specific identification of amyloid fibrils using chiroptical effects in plasmonic nanoparticles. The formation of amyloid fibrils based on α-synuclein was probed using gold nanorods, which showed no apparent interaction with monomeric proteins but effective adsorption onto fibril structures via noncovalent interactions...
March 12, 2018: Proceedings of the National Academy of Sciences of the United States of America
José A Del Río, Isidre Ferrer, Rosalina Gavín
Several studies have indicated that certain misfolded amyloids composed of tau, β-amyloid or α-synuclein can be transferred from cell to cell, suggesting the contribution of mechanisms reminiscent of those by which infective prions spread through the brain. This process of a 'prion-like' spreading between cells is also relevant as a novel putative therapeutic target that could block the spreading of proteinaceous aggregates throughout the brain which may underlie the progressive nature of neurodegenerative diseases...
March 9, 2018: Progress in Neurobiology
Liying Li, J P McGinnis, Kausik Si
Prion-like proteins overlap with intrinsically disordered and low-complexity sequence families. These proteins are widespread, especially among mRNA-binding proteins. A salient feature of these proteins is the ability to form protein assemblies with distinct biophysical and functional properties. While prion-like proteins are involved in myriad of cellular processes, we propose potential roles for protein assemblies in regulated protein synthesis. Since proteins are the ultimate functional output of gene expression, when, where, and how much of a particular protein is made dictates the functional state of a cell...
March 9, 2018: Trends in Cell Biology
Sing-Hui Ong, Kai-Wey Goh, Cornelius Kwang-Lee Chieng, Yee-How Say
Background: Tumor-induced angiogenesis is an imperative event in pledging new vasculature for tumor metastasis. Since overexpression of neuronal proteins gamma-synuclein (γ-Syn) and cellular prion protein (PrPC ) is always detected in advanced stages of cancer diseases which involve metastasis, this study aimed to investigate whether γ-Syn or PrPC overexpression in colorectal adenocarcinoma, LS 174T cells affects angiogenesis of endothelial cells, EA.hy 926 (EA). Methods: EA cells were treated with conditioned media (CM) of LS 174T-γ-Syn or LS 174T-PrP, and their proliferation, invasion, migration, adhesion and ability to form angiogenic tubes were assessed using a range of biological assays...
2018: PeerJ
Yann Gambin, Nichole Giles, Ailís O'Carroll, Mark E Polinkovsky, Dominic J B Hunter, Emma Sierecki
No abstract text is available yet for this article.
March 8, 2018: Journal of Molecular Biology
Richard Salazar
INTRODUCTION: Sporadic Creutzfeldt-Jakob disease is a prion disease characterized by rapidly progressive dementia, ataxia and myoclonus. Atypical phenotype masquerading as stroke, movement disorders or autoimmune encephalitis have been described. Here, I report a probable case of sCJD with an atypical presentation associated with anti-Zic4 antibody and review the literature of neuronal antibodies in CJD. CASE REPORT: A 70 year-old gentleman is admitted with a 2-month history of recurrent stroke-like symptoms associated with behavioral disturbances, gait ataxia and rapidly progressive dementia...
March 5, 2018: Clinical Neurology and Neurosurgery
Edgar E Boczek, Simon Alberti
Small heat shock proteins (sHsps) are adenosine triphosphate-independent chaperones that protect cells from misfolded proteins. In this issue, Grousl et al. (2018. J. Cell Biol. show that the yeast sHsp Hsp42 uses a prion-like intrinsically disordered domain to bind and sequester misfolded proteins in protein deposition sites.
March 9, 2018: Journal of Cell Biology
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