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https://www.readbyqxmd.com/read/28550528/prion-like-seeding-of-misfolded-%C3%AE-synuclein-in-the-brains-of-dementia-with-lewy-body-patients-in-rt-quic
#1
Kazunori Sano, Ryuichiro Atarashi, Katsuya Satoh, Daisuke Ishibashi, Takehiro Nakagaki, Yasushi Iwasaki, Mari Yoshida, Shigeo Murayama, Kenichi Mishima, Noriyuki Nishida
The prion-like seeding of misfolded α-synuclein (αSyn) involved in the pathogenesis of Lewy body diseases (LBD) remains poorly understood at the molecular level. Using the real-time quaking-induced conversion (RT-QUIC) seeding assay, we investigated whether brain tissues from cases of dementia with Lewy bodies (DLB), which contain serine 129 (Ser129)-phosphorylated insoluble aggregates of αSyn, can convert Escherichia coli-derived recombinant αSyn (r-αSyn) to fibrils. Diffuse neocortical DLB yielded 50% seeding dose (SD50) values of 10(7)~10(10)/g brain...
May 26, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28549585/cystamine-mediated-inhibition-of-protein-disulfide-isomerase-triggers-aggregation-of-misfolded-orexin-a-in-the-golgi-apparatus-and-prevents-extracellular-secretion-of-orexin-a
#2
Issei Fujita, Mizuki Nobunaga, Takahiro Seki, Yuki Kurauchi, Akinori Hisatsune, Hiroshi Katsuki
Orexins (orexin-A and orexin-B) are neuropeptides that are reduced in narcolepsy, a sleep disorder that is characterized by excessive daytime sleepiness, sudden sleep attacks and cataplexy. However, it remains unclear how orexins in the brain and orexin neurons are reduced in narcolepsy. Orexin-A has two closely located intramolecular disulfide bonds and is prone to misfolding due to the formation of incorrect disulfide bonds. Protein disulfide isomerase (PDI) possesses disulfide interchange activity. PDI can modify misfolded orexin-A to its native form by rearrangement of two disulfide bonds...
May 23, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28549094/a-novel-dominant-mutation-in-sag-the-arrestin-1-gene-is-a-common-cause-of-retinitis-pigmentosa-in-hispanic-families-in-the-southwestern-united-states
#3
Lori S Sullivan, Sara J Bowne, Daniel C Koboldt, Elizabeth L Cadena, John R Heckenlively, Kari E Branham, Dianna H Wheaton, Kaylie D Jones, Richard S Ruiz, Mark E Pennesi, Paul Yang, David Davis-Boozer, Hope Northrup, Vsevold V Gurevich, Rui Chen, Mingchu Xu, Yumei Li, David G Birch, Stephen P Daiger
Purpose: To identify the causes of autosomal dominant retinitis pigmentosa (adRP) in a cohort of families without mutations in known adRP genes and consequently to characterize a novel dominant-acting missense mutation in SAG. Methods: Patients underwent ophthalmologic testing and were screened for mutations using targeted-capture and whole-exome next-generation sequencing. Confirmation and additional screening were done by Sanger sequencing. Haplotypes segregating with the mutation were determined using short tandem repeat and single nucleotide variant polymorphisms...
May 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28548229/endoplasmic-reticulum-stress-in-the-heart-the-insights-into-mechanisms-and-drug-targets
#4
REVIEW
Shunyao Wang, Pablo Binder, Qiru Fang, Zhenzhong Wang, Wei Xiao, Wei Liu, Xin Wang
The endoplasmic reticulum (ER) serves several essential cellular functions including protein synthesis, protein folding, protein translocation, calcium homoeostasis and lipid biosynthesis. Physiological or pathological stimuli which disrupt ER homoeostasis and disturb its functions lead to an accumulation of misfolded and unfolded proteins, a condition referred to as ER stress. ER stress triggers unfolded protein response (UPR) to restore the homoeostasis of ER through activating transcriptional and translational pathways...
May 26, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28546074/outcomes-from-autologous-hematopoietic-cell-transplantation-versus-chemotherapy-alone-for-the-management-of-light-chain-al-amyloidosis
#5
Oluchi Oke, Tarsheen Sethi, Stacey Goodman, Sharon Phillips, Ilka Decker, Samuel Rubinstein, Beatrice Concepcion, Sarah Horst, Madan Jagasia, Adetola Kassim, Shelton L Harrell, Anthony Langone, Daniel Lenihan, Kyle T Rawling, David Slosky, R Frank Cornell
Light chain amyloidosis (AL) results in tissue deposition of misfolded proteins causing organ dysfunction. In an era of modern therapies such as bortezomib, reassessment of the benefit of autologous hematopoietic cell transplantation (AHCT) should be considered. This study compares the difference in outcomes between patients with AL receiving chemotherapy alone (CT) vs. AHCT. Seventy-four patients with AL were retrospectively analyzed. Two cohorts of patients were studied, those receiving CT (n=31) or AHCT (n=43)...
May 22, 2017: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/28545479/endoplasmic-reticulum-stress-and-inflammation-in-the-central-nervous-system
#6
REVIEW
Neil T Sprenkle, Savannah G Sims, Cristina L Sánchez, Gordon P Meares
Persistent endoplasmic reticulum (ER) stress is thought to drive the pathology of many chronic disorders due to its potential to elicit aberrant inflammatory signaling and facilitate cell death. In neurodegenerative diseases, the accumulation of misfolded proteins and concomitant induction of ER stress in neurons contributes to neuronal dysfunction. In addition, ER stress responses induced in the surrounding neuroglia may promote disease progression by coordinating damaging inflammatory responses, which help fuel a neurotoxic milieu...
May 25, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28545464/c10orf10-depp-mediated-ros-accumulation-is-a-critical-modulator-of-foxo3-induced-autophagy
#7
S Salcher, M Hermann, U Kiechl-Kohlendorfer, M J Ausserlechner, P Obexer
BACKGROUND: Neuroblastoma is the most common solid tumor in childhood and develops from undifferentiated progenitor cells of the sympathetic nervous system. In neuronal tumor cells DNA-damaging chemotherapeutic agents activate the transcription factor FOXO3 which regulates the formation of reactive oxygen species (ROS) and cell death as well as a longevity program associated with therapy resistance. We demonstrated before that C10ORF10/DEPP, a transcriptional target of FOXO3, localizes to peroxisomes and mitochondria and impairs cellular ROS detoxification...
May 25, 2017: Molecular Cancer
https://www.readbyqxmd.com/read/28545141/prion-pathogenesis-is-unaltered-in-the-absence-of-sirp%C3%AE-mediated-don-t-eat-me-signaling
#8
Mario Nuvolone, Marta Paolucci, Silvia Sorce, Veronika Kana, Rita Moos, Takashi Matozaki, Adriano Aguzzi
Prion diseases are neurodegenerative conditions caused by misfolding of the prion protein, leading to conspicuous neuronal loss and intense microgliosis. Recent experimental evidence point towards a protective role of microglia against prion-induced neurodegeneration, possibly through elimination of prion-containing apoptotic bodies. The molecular mechanisms by which microglia recognize and eliminate apoptotic cells in the context of prion diseases are poorly defined. Here we investigated the possible involvement of signal regulatory protein α (SIRPα), a key modulator of host cell phagocytosis; SIRPα is encoded by the Sirpa gene that is genetically linked to the prion gene Prnp...
2017: PloS One
https://www.readbyqxmd.com/read/28544119/common-fibril-structures-imply-systemically-conserved-protein-misfolding-pathways-in%C3%A2-vivo
#9
Karthikeyan Annamalai, Falk Liberta, Marie-Theres Vielberg, William Close, Hauke Lilie, Karl-Heinz Gührs, Angelika Schierhorn, Rolf Koehler, Andreas Schmidt, Christian Haupt, Ute Hegenbart, Stefan Schönland, Matthias Schmidt, Michael Groll, Marcus Fändrich
Systemic amyloidosis is caused by the misfolding of a circulating amyloid precursor protein and the deposition of amyloid fibrils in multiple organs. Chemical and biophysical analysis of amyloid fibrils from human AL and murine AA amyloidosis reveal the same fibril morphologies in different tissues or organs of one patient or diseased animal. The observed structural similarities concerned the fibril morphology, the fibril protein primary and secondary structures, the presence of post-translational modifications and, in case of the AL fibrils, the partially folded characteristics of the polypeptide chain within the fibril...
May 23, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28542401/molecular-dynamics-analysis-of-the-aggregation-propensity-of-polyglutamine-segments
#10
Jingran Wen, Daniel R Scoles, Julio C Facelli
Protein misfolding and aggregation is a pathogenic feature shared among at least ten polyglutamine (polyQ) neurodegenerative diseases. While solvent-solution interaction is a key factor driving protein folding and aggregation, the solvation properties of expanded polyQ tracts are not well understood. By using GPU-enabled all-atom molecular dynamics simulations of polyQ monomers in an explicit solvent environment, this study shows that solvent-polyQ interaction propensity decreases as the lengths of polyQ tract increases...
2017: PloS One
https://www.readbyqxmd.com/read/28540657/uch-l1-inhibition-suppresses-tau-aggresome-formation-during-proteasomal-impairment
#11
Quntao Yu, Hongmao Zhang, Yuan Li, Chao Liu, Shaohui Wang, Xiaomei Liao
In conditions of proteasomal impairment, the damaged or misfolded proteins, collectively known as aggresome, can accumulate in the perinuclear space and be subsequently eliminated by autophagy. Abnormal aggregation of microtubule-associated protein tau in the cytoplasm is a common neuropathological feature of tauopathies. The deficiency in ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), a proteasomal deubiquitinating enzyme, is closely related to tau aggregation; however, the associated mechanisms remain unclear...
May 24, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28539871/protein-quality-control-and-the-amyotrophic-lateral-sclerosis-frontotemporal-dementia-continuum
#12
Hamideh Shahheydari, Audrey Ragagnin, Adam K Walker, Reka P Toth, Marta Vidal, Cyril J Jagaraj, Emma R Perri, Anna Konopka, Jessica M Sultana, Julie D Atkin
Protein homeostasis, or proteostasis, has an important regulatory role in cellular function. Protein quality control mechanisms, including protein folding and protein degradation processes, have a crucial function in post-mitotic neurons. Cellular protein quality control relies on multiple strategies, including molecular chaperones, autophagy, the ubiquitin proteasome system, endoplasmic reticulum (ER)-associated degradation (ERAD) and the formation of stress granules (SGs), to regulate proteostasis. Neurodegenerative diseases are characterized by the presence of misfolded protein aggregates, implying that protein quality control mechanisms are dysfunctional in these conditions...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28539581/peripherin-2-and-rom-1-have-opposing-effects-on-rod-outer-segment-targeting-of-retinitis-pigmentosa-linked-peripherin-2-mutants
#13
Sybille Böhm, Lisa M Riedmayr, O N Phuong Nguyen, Andreas Gießl, Toni Liebscher, Elisabeth S Butz, Christian Schön, Stylianos Michalakis, Christian Wahl-Schott, Martin Biel, Elvir Becirovic
Mutations in the photoreceptor outer segment (OS) specific peripherin-2 lead to autosomal dominant retinitis pigmentosa (adRP). By contrast, mutations in the peripherin-2 homolog Rom-1 cause digenic RP in combination with certain heterozygous mutations in peripherin-2. The mechanisms underlying the differential role of peripherin-2 and Rom-1 in RP pathophysiology remained elusive so far. Here, focusing on two adRP-linked peripherin-2 mutants, P210L and C214S, we analyzed the binding characteristics, protein assembly, and rod OS targeting of wild type (per(WT)), mutant peripherin-2 (per(MT)), or Rom-1 complexes, which can be formed in patients heterozygous for peripherin-2 mutations...
May 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28539529/membrane-trafficking-illuminates-a-path-to-parkinson-s-disease
#14
Takafumi Hasegawa, Naoto Sugeno, Akio Kikuchi, Toru Baba, Masashi Aoki
Parkinson's disease (PD) is the second most common neurodegenerative disorder that is characterized by progressive movement disability and a variety of non-motor symptoms. The neuropathology of PD consists of the loss of dopaminergic neurons in the midbrain and the appearance of neuronal inclusions called Lewy bodies, which contain insoluble α-synuclein, a relatively small protein originally identified in association with synaptic vesicles in the presynaptic nerve terminals. Drugs that replenish dopamine can partly alleviate the motor symptoms, but they do not cure the disease itself...
2017: Tohoku Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28539470/the-src-c-abl-pathway-is-a-potential-therapeutic-target-in-amyotrophic-lateral-sclerosis
#15
Keiko Imamura, Yuishin Izumi, Akira Watanabe, Kayoko Tsukita, Knut Woltjen, Takuya Yamamoto, Akitsu Hotta, Takayuki Kondo, Shiho Kitaoka, Akira Ohta, Akito Tanaka, Dai Watanabe, Mitsuya Morita, Hiroshi Takuma, Akira Tamaoka, Tilo Kunath, Selina Wray, Hirokazu Furuya, Takumi Era, Kouki Makioka, Koichi Okamoto, Takao Fujisawa, Hideki Nishitoh, Kengo Homma, Hidenori Ichijo, Jean-Pierre Julien, Nanako Obata, Masato Hosokawa, Haruhiko Akiyama, Satoshi Kaneko, Takashi Ayaki, Hidefumi Ito, Ryuji Kaji, Ryosuke Takahashi, Shinya Yamanaka, Haruhisa Inoue
Amyotrophic lateral sclerosis (ALS), a fatal disease causing progressive loss of motor neurons, still has no effective treatment. We developed a phenotypic screen to repurpose existing drugs using ALS motor neuron survival as readout. Motor neurons were generated from induced pluripotent stem cells (iPSCs) derived from an ALS patient with a mutation in superoxide dismutase 1 (SOD1). Results of the screen showed that more than half of the hits targeted the Src/c-Abl signaling pathway. Src/c-Abl inhibitors increased survival of ALS iPSC-derived motor neurons in vitro...
May 24, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28539446/infectious-prions-in-the-pregnancy-microenvironment-of-cwd-infected-reeves-muntjac-deer
#16
Amy V Nalls, Erin McNulty, Clare E Hoover, Laura A Pulscher, Edward A Hoover, Candace K Mathiason
Ample evidence exists for the presence of infectious agents at the maternal-fetal interface, often with grave outcomes to the developing fetus (i.e. zika virus, brucella, cytomegalovirus, toxoplasma). While less studied, pregnancy-related transmissible spongiform encephalopathies (TSEs) have been implicated in several species, including humans. Our previous work has shown that prions can be transferred from mother-to-offspring resulting in the development of clinical TSE disease in offspring born to CWD-infected muntjac dams (64)...
May 24, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28539411/substrate-binding-by-the-yeast-hsp110-nucleotide-exchange-factor-and-molecular-chaperone-sse1-is-not-obligate-for-its-biological-activities
#17
Veronica M Garcia, Nadinath B Nillegoda, Bernd Bukau, Kevin A Morano
The highly conserved heat-shock protein 70 (Hsp70) is a ubiquitous molecular chaperone essential for maintaining cellular protein homeostasis. The related protein Hsp110 (Sse1/Sse2 in Saccharomyces cerevisiae) functions as a nucleotide exchange factor (NEF) to regulate the protein folding activity of Hsp70. Hsp110/Sse1 can additionally prevent protein aggregation in vitro via its substrate binding domain (SBD), but the cellular roles of this "holdase" activity remain poorly defined. We generated and characterized an Sse1 mutant that separates, for the first time, its nucleotide exchange and substrate binding functions...
May 24, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28539401/transmembrane-helix-hydrophobicity-is-an-energetic-barrier-during-the-retrotranslocation-of-integral-membrane-erad-substrates
#18
Christopher J Guerriero, Karl-Richard Reutter, Andrew A Augustine, G Michael Preston, Kurt F Weiberth, Timothy D Mackie, Hillary C Cleveland-Rubeor, Neville P Bethel, Keith M Callenberg, Kunio Nakatsukasa, Michael Grabe, Jeffrey L Brodsky
Integral membrane proteins fold inefficiently and are susceptible to turnover via the endoplasmic reticulum-associated degradation (ERAD) pathway. During ERAD, misfolded proteins are recognized by molecular chaperones, polyubiquitinated, and retrotranslocated to the cytoplasm for proteasomal degradation. Although many aspects of this pathway are defined, how transmembrane helices (TMHs) are removed from the membrane and into the cytoplasm prior to degradation is poorly understood. In this study, we asked whether the hydrophobic character of a TMH acts as an energetic barrier to retrotranslocation...
May 24, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28539119/towards-the-concept-of-disease-modifier-in-post-stroke-or-vascular-cognitive-impairment-a-consensus-report
#19
Régis Bordet, Ralf Ihl, Amos D Korczyn, Giuseppe Lanza, Jelka Jansa, Robert Hoerr, Alla Guekht
BACKGROUND: Vascular cognitive impairment (VCI) is a complex spectrum encompassing post-stroke cognitive impairment (PSCI) and small vessel disease-related cognitive impairment. Despite the growing health, social, and economic burden of VCI, to date, no specific treatment is available, prompting the introduction of the concept of a disease modifier. CONSENSUS AND SUGGESTIONS: Within this clinical spectrum, VCI and PSCI remain advancing conditions as neurodegenerative diseases with progression of both vascular and degenerative lesions accounting for cognitive decline...
May 24, 2017: BMC Medicine
https://www.readbyqxmd.com/read/28539049/assembly-of-huntingtin-headpiece-into-%C3%AE-helical-bundles
#20
Beytullah Ozgur, Mehmet Sayar
Protein aggregation is a hallmark of neurodegenerative disorders. In this group of brain-related disorders, a disease-specific "host" protein or fragment misfolds and adopts a metastatic, aggregate-prone conformation. Often, this misfolded conformation is structurally and thermodynamically different from its native state. Intermolecular contacts, which arise in this non-native state, promote aggregation. In this regard, understanding the molecular principles and mechanisms that lead to the formation of such a non-native state and further promote the formation of the critical nucleus for fiber growth is essential...
May 24, 2017: Biointerphases
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