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https://www.readbyqxmd.com/read/28719185/small-molecule-enhancement-of-20s-proteasome-activity-targets-intrinsically-disordered-proteins
#1
Corey L Jones, Evert Njomen, Benita Sjogren, Thomas S Dexheimer, Jetze J Tepe
The 20S proteasome is the main protease for degradation of oxidatively damaged and intrinsically disordered proteins. When accumulation of disordered or oxidatively damaged proteins exceed proper clearance in neurons, imbalanced pathway signaling or aggregation occurs, which have been implicated in the pathogenesis of several neurological disor-ders. Screening of the NIH Clinical Collection and Prestwick libraries identified the neuroleptic agent chlorpromazine as a lead agent capable of enhancing 20S proteasome activity...
July 18, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28715596/influence-of-physical-exercise-on-%C3%AE-amyloid-%C3%AE-synuclein-and-tau-accumulation-an-in-vitro-model-of-oxidative-stress-in-human-red-blood-cells
#2
C Iofrida, S Daniele, D Pietrobono, J Fusi, F Galetta, M L Trincavelli, U Bonuccelli, F Franzoni, C Martini
A common pathological feature of neurodegenerative disorders (NDs), such as Alzheimer's (AD) and Parkinson's (PD) diseases, is the abnormal accumulation and misfolding of specific proteins, primarily α-synuclein (α-syn), β-amyloid1-42 (Aβ) and tau, in brain and in peripheral tissues too. Oxidative stress has been proved to be involved in NDs at various levels and, in particular, in such protein alterations, on the contrary physical activity is emerging as a counteracting factor in NDs. In the present work, the content of Aβ, α-syn and tau in red blood cells (RBCs) derived from ten endurance athletes (ATHL) and ten sedentary volunteers (SED) were compared before and after in vitrooxidative stress treatment...
July 1, 2017: Archives Italiennes de Biologie
https://www.readbyqxmd.com/read/28713240/the-coordinated-action-of-calcineurin-and-cathepsin-d-protects-against-%C3%AE-synuclein-toxicity
#3
Andreas Aufschnaiter, Lukas Habernig, Verena Kohler, Jutta Diessl, Didac Carmona-Gutierrez, Tobias Eisenberg, Walter Keller, Sabrina Büttner
The degeneration of dopaminergic neurons during Parkinson's disease (PD) is intimately linked to malfunction of α-synuclein (αSyn), the main component of the proteinaceous intracellular inclusions characteristic for this pathology. The cytotoxicity of αSyn has been attributed to disturbances in several biological processes conserved from yeast to humans, including Ca(2+) homeostasis, general lysosomal function and autophagy. However, the precise sequence of events that eventually results in cell death remains unclear...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28711596/the-relevance-of-contact-independent-cell-to-cell-transfer-of-tdp-43-and-sod1-in-amyotrophic-lateral-sclerosis
#4
REVIEW
Maya A Hanspal, Christopher M Dobson, Justin J Yerbury, Janet R Kumita
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease involving the formation of cytoplasmic aggregates by proteins including TDP-43 and SOD1, in affected cells in the central nervous system (CNS). Pathology spreads from an initial site of onset to contiguous anatomical regions. There is evidence that for disease-associated proteins, including TDP-43 and SOD1, non-native protein conformers can promote misfolding of the natively folded counterparts, and cell-to-cell transfer of pathological aggregates may underlie the spread of the disease throughout the CNS...
July 12, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28711409/nortriptyline-inhibits-aggregation-and-neurotoxicity-of-alpha-synuclein-by-enhancing-reconfiguration-of-the-monomeric-form
#5
Timothy J Collier, Kinshuk R Srivastava, Craig Justman, Tom Grammatopoulous, Birgit Hutter-Paier, Manuela Prokesch, Daniel Havas, Jean-Christophe Rochet, Fang Liu, Kevin Jock, Patrícia de Oliveira, Georgia L Stirtz, Ulf Dettmer, Caryl E Sortwell, Mel B Feany, Peter Lansbury, Lisa Lapidus, Katrina L Paumier
The pathology of Parkinson's disease and other synucleinopathies is characterized by the formation of intracellular inclusions comprised primarily of misfolded, fibrillar α-synuclein (α-syn). One strategy to slow disease progression is to prevent the misfolding and aggregation of its native monomeric form. Here we present findings that support the contention that the tricyclic antidepressant compound nortriptyline (NOR) has disease-modifying potential for synucleinopathies. Findings from in vitro aggregation and kinetics assays support the view that NOR inhibits aggregation of α-syn by directly binding to the soluble, monomeric form, and by enhancing reconfiguration of the monomer, inhibits formation of toxic conformations of the protein...
July 12, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28711405/a-unique-glycan-isoform-of-transferrin-in-cerebrospinal-fluid-a-potential-diagnostic-marker-for-neurological-diseases
#6
REVIEW
Kyoka Hoshi, Hiromi Ito, Yuka Matsumoto, Kiyoshi Saito, Takashi Honda, Yoshiki Yamaguchi, Yasuhiro Hashimoto
BACKGROUND: cerebrospinal fluid (CSF) is sequestered from blood by the blood-brain barrier and directly communicates with brain parenchymal interstitial fluid, leading to contain specific biomarkers of neurological diseases. SCOPE OF REVIEW: CSF contains glycan isoforms of transferrin (Tf): one appears to be derived from the brain and the other from blood. MAJOR CONCLUSIONS: CSF contains two glycan-isoforms; brain-type Tf and serum-type Tf...
July 12, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28710275/a-ph-dependent-switch-promotes-%C3%AE-synuclein-fibril-formation-via-glutamate-residues
#7
Gina M Moriarty, Michael P Olson, Tamr B Atieh, Maria K Janowska, Sagar D Khare, Jean Baum
Alpha-synuclein (αS) is the primary protein associated with Parkinson's disease, and undergoes aggregation from its intrinsically disordered monomeric form to a cross-β fibrillar form. The closely related homolog beta-synuclein (βS) is essentially fibril resistant under cytoplasmic physiological conditions. Toxic gain of function by βS has been linked to dysfunction, but the aggregation behavior of βS under altered pH is not well understood. In this work, we compare fibril formation of αS and βS at pH 7...
July 14, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28707886/diarylheptanoids-from-rhizomes-of-alpinia-officinarum-inhibit-aggregation-of-alpha-synuclein
#8
Guangmiao Fu, Wei Zhang, Dongsheng Du, Yu Pong Ng, Fanny C F Ip, Rongbiao Tong, Nancy Y Ip
Two new diarylheptanoids, alpinins A (1) and B (2), together with eighteen known diarylheptanoids (3-20), were isolated from the rhizomes of Alpinia officinarum. Their structures were elucidated by comprehensive spectroscopic analysis including HRMS, IR, and 1D- and 2D-NMR. Structurally, alpinin A is a new member of the small family of oxa-bridged diarylheptanoids and contains the characteristic 2,6-cis-configured tetrahydropyran motif (C1-C5 oxa-bridge). The absolute configuration of alpinin A was confirmed by asymmetric total synthesis of the enantiomer (ent-1), corroborating the assignment of the molecular structure...
July 14, 2017: Journal of Agricultural and Food Chemistry
https://www.readbyqxmd.com/read/28706191/aldehyde-dehydrogenase-1-positive-nigrostriatal-dopaminergic-fibers-exhibit-distinct-projection-pattern-and-dopamine-release-dynamics-at-mouse-dorsal-striatum
#9
Carmelo Sgobio, Junbing Wu, Wang Zheng, Xi Chen, Jing Pan, Armando G Salinas, Margaret I Davis, David M Lovinger, Huaibin Cai
Aldehyde dehydrogenase 1 (ALDH1A1)-positive dopaminergic (DA) neurons at the ventral substantia nigra pars compacta (SNpc) preferentially degenerate in Parkinson's disease (PD). Their projection pattern and dopamine release properties, however, remains uncharacterized. Here we show that ALDH1A1-positive axons project predominantly to the rostral two-thirds of dorsal striatum. A portion of these axons converge on a small fraction of striosome compartments restricted to the dorsolateral striatum (DLS), where less dopamine release was measured compared to the adjacent matrix enriched with the ALDH1A1-negative axons...
July 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28702523/implications-of-peptide-assemblies-in-amyloid-diseases
#10
REVIEW
Pu Chun Ke, Marc-Antonie Sani, Feng Ding, Aleksandr Kakinen, Ibrahim Javed, Frances Separovic, Thomas P Davis, Raffaele Mezzenga
Neurodegenerative disorders and type 2 diabetes are global epidemics compromising the quality of life of millions worldwide, with profound social and economic implications. Despite the significant differences in pathology - much of which are poorly understood - these diseases are commonly characterized by the presence of cross-β amyloid fibrils as well as the loss of neuronal or pancreatic β-cells. In this review, we document research progress on the molecular and mesoscopic self-assembly of amyloid-beta, alpha synuclein, human islet amyloid polypeptide and prions, the peptides and proteins associated with Alzheimer's, Parkinson's, type 2 diabetes and prion diseases...
July 12, 2017: Chemical Society Reviews
https://www.readbyqxmd.com/read/28700687/secretory-carrier-membrane-protein-5-is-an-autophagy-inhibitor-that-promotes-the-secretion-of-%C3%AE-synuclein-via-exosome
#11
Yi Yang, Meiling Qin, Puhua Bao, Wangchao Xu, Jin Xu
Autophagy-lysosomal pathway is a cellular protective system to remove aggregated proteins and damaged organelles. Meanwhile, exosome secretion has emerged as a mode to selectively clear the neurotoxic proteins, such as α-synuclein. Mounting evidence suggests that these two cellular processes are coordinated to facilitate the clearance of toxic cellular waste; however the regulators for the transition between these two processes are unclear. Here we show that SCAMP5, a secretory carrier membrane protein significantly induced in the brains of Huntington's disease patients, is quickly and transiently induced by protein stress and autophagic stimulation, and is regulated by the master autophagy transcriptional regulator TFEB...
2017: PloS One
https://www.readbyqxmd.com/read/28698628/%C3%AE-synuclein-control-of-mitochondrial-homeostasis-in-human-derived-neurons-is-disrupted-by-mutations-associated-with-parkinson-s-disease
#12
Victorio Martin Pozo Devoto, Nicolas Dimopoulos, Matías Alloatti, María Belén Pardi, Trinidad M Saez, María Gabriela Otero, Lucas Eneas Cromberg, Antonia Marín-Burgin, Maria Elida Scassa, Gorazd B Stokin, Alejandro F Schinder, Gustavo Sevlever, Tomás Luis Falzone
The etiology of Parkinson's disease (PD) converges on a common pathogenic pathway of mitochondrial defects in which α-Synuclein (αSyn) is thought to play a role. However, the mechanisms by which αSyn and its disease-associated allelic variants cause mitochondrial dysfunction remain unknown. Here, we analyzed mitochondrial axonal transport and morphology in human-derived neurons overexpressing wild-type (WT) αSyn or the mutated variants A30P or A53T, which are known to have differential lipid affinities...
July 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28698377/monomeric-and-fibrillar-%C3%AE-synuclein-exert-opposite-effects-on-the-catalytic-cycle-that-promotes-the-proliferation-of-a%C3%AE-42-aggregates
#13
Sean Chia, Patrick Flagmeier, Johnny Habchi, Veronica Lattanzi, Sara Linse, Christopher M Dobson, Tuomas P J Knowles, Michele Vendruscolo
The coaggregation of the amyloid-β peptide (Aβ) and α-synuclein is commonly observed in a range of neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. The complex interplay between Aβ and α-synuclein has led to seemingly contradictory results on whether α-synuclein promotes or inhibits Aβ aggregation. Here, we show how these conflicts can be rationalized and resolved by demonstrating that different structural forms of α-synuclein exert different effects on Aβ aggregation. Our results demonstrate that whereas monomeric α-synuclein blocks the autocatalytic proliferation of Aβ42 (the 42-residue form of Aβ) fibrils, fibrillar α-synuclein catalyses the heterogeneous nucleation of Aβ42 aggregates...
July 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28696461/room-temperature-in-cell-epr-spectroscopy-alpha-synuclein-disease-variants-remain-intrinsically-disordered-in-the-cell
#14
Julia Cattani, Vinod Subramaniam, Malte Drescher
Human alpha-Synuclein (aS), implicated in Parkinson's disease, adopts a rich variety of different conformations depending on the macromolecular context. In order to unravel its pathophysiological role, monitoring its intracellular conformational state and identifying differences for the disease variants is crucial. Here, we present an intracellular spectroscopy approach based on a systematic spin-labeling site-scan in combination with intracellular electron paramagnetic resonance spectroscopy determining conformations on a molecular scale...
July 11, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/28696167/neuroprotective-effect-of-%C3%AE-mangostin-on-mitochondrial-dysfunction-and-%C3%AE-synuclein-aggregation-in-rotenone-induced-model-of-parkinson-s-disease-in-differentiated-sh-sy5y-cells
#15
Xin-Mei Hao, Lian-Da Li, Chang-Ling Duan, Yu-Juan Li
The study was designed to evaluate the protective effect of α-mangostin and explore its mechanism in an in vitro model of Parkinson's disease (PD) induced by rotenone. SH-SY5Y cells were treated with rotenone and α-mangostin for 24 h. α-Mangostin significantly and concentration-dependently inhibited rotenone-induced cytotoxicity. The rotenone-induced aggregation of α-synuclein and loss of TH were alleviated by α-mangostin. α-Mangostin treatment also reversed the rotenone-induced overproduction of reactive oxygen species, activation of caspases (-8 and -3) and mitochondrial dysfunction, reflected by decrease in mitochondrial membrane potential and cellular ATP levels...
August 2017: Journal of Asian Natural Products Research
https://www.readbyqxmd.com/read/28695482/role-of-apolipoproteins-and-%C3%AE-synuclein-in-parkinson-s-disease
#16
REVIEW
Fatemeh Nouri Emamzadeh
Parkinson's disease (PD) is a progressive brain disorder that interferes with activities of normal life. The main pathological feature of this disease is the loss of more than 80% of dopamine-producing neurons in the substantia nigra (SN). Dopaminergic neuronal cell death occurs when intraneuronal, insoluble, aggregated proteins start to form Lewy bodies (LBs), the most important component of which is a protein called α-synuclein (α-syn). α-Syn structurally contains hexameric repeats of 11 amino acids, which are characteristic of apolipoproteins and thus α-syn can also be considered an apolipoprotein...
July 10, 2017: Journal of Molecular Neuroscience: MN
https://www.readbyqxmd.com/read/28691859/preliminary-studies-of-berberine-and-its-semi-synthetic-derivatives-as-a-promising-class-of-multi-target-anti-parkinson-agents
#17
Giovanni Ribaudo, Enrico Zanforlin, Marcella Canton, Sergio Bova, Giuseppe Zagotto
Parkinson's disease (PD) is a neurodegenerative disorder bearing motor and nonmotor symptoms. The treatment today is symptomatical rather than preventive or curative and this leaves the field open for the search of both novel molecular targets and drug candidates. Interference with α-synuclein fibrillation, monoamine oxidase (MAO) inhibition, modulation of adenosine receptors and the inhibition of specific phosphodiesterase (PDE) isoforms are some of the currently pursued strategies. We synthesised and studied some semi-synthetic berberine derivatives using a set of in silico tools...
July 10, 2017: Natural Product Research
https://www.readbyqxmd.com/read/28691818/cu-ii-binding-sites-in-n-terminally-acetylated-%C3%AE-synuclein-a-theoretical-rationalization
#18
Rafael Ramis, Joaquin Ortega-Castro, Bartolomé Vilanova, Miquel Adrover, Juan Frau
The interactions between N-terminally acetylated α-synuclein and Cu(II) at several binding sites have been studied with DFT calculations, specically with the M06 hybrid functional and the wB97X-D DFT-D functional. In previous experimental studies, Cu(II) was shown to bind several a-synuclein residues, including Met1-Asp2 and His50, forming square planar coordination complexes. Also, it was determined that a low-affinity binding site exists in the C-terminal domain, centered on Asp121. However, in the N-terminally acetylated protein, present in vivo, the Met1 site is blocked...
July 10, 2017: Journal of Physical Chemistry. A
https://www.readbyqxmd.com/read/28690195/low-molar-excess-of-4-oxo-2-nonenal-and-4-hydroxy-2-nonenal-promote-oligomerization-of-alpha-synuclein-through-different-pathways
#19
Leire Almandoz-Gil, Hedvig Welander, Elisabet Ihse, Payam Emami Khoonsari, Sravani Musunuri, Christofer Lendel, Jessica Sigvardson, Mikael Karlsson, Martin Ingelsson, Kim Kultima, Joakim Bergström
Aggregated alpha-synuclein is the main component of Lewy bodies, intraneuronal inclusions found in brains with Parkinson's disease and dementia with Lewy bodies. A body of evidence implicates oxidative stress in the pathogenesis of these diseases. For example, a large excess (30:1, aldehyde:protein) of the lipid peroxidation end products 4-oxo-2-nonenal (ONE) or 4-hydroxy-2-nonenal (HNE) can induce alpha-synuclein oligomer formation. The objective of the study was to investigate the effect of these reactive aldehydes on alpha-synuclein at a lower molar excess (3:1) at both physiological (7...
July 6, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28687316/levodopa-l-dopa-attenuates-endoplasmic-reticulum-stress-response-and-cell-death-signaling-through-drd2-in-sh-sy5y-neuronal-cells-under-%C3%AE-synuclein-induced-toxicity
#20
Juhyun Song, Byeong C Kim, Dai-Trang T Nguyen, Manikandan Samidurai, Seong-Min Choi
Parkinson's disease (PD) is characterized by the formation of Lewy bodies (LBs) in dopaminergic neurons. α-Synuclein (α-syn), a major protein component of LBs, is known to regulate synaptic plasticity, with a crucial role in memory and motor function in the central nervous system. Levodopa (L-3,4-dihydroxyphenylalanine; also known as L-DOPA) is considered the most effective medication for controlling the symptoms of PD. However, it is unclear whether L-DOPA improves the neuropathology of PD. In the present study, we investigated the effect of L-DOPA on SH-SY5Y neuronal cells under α-syn-induced toxicity...
July 4, 2017: Neuroscience
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