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synuclein and aggregation

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https://www.readbyqxmd.com/read/28931065/chlamydomonas-fap265-is-a-tubulin-polymerization-promoting-protein-essential-for-flagellar-reassembly-and-hatching-of-daughter-cells-from-the-sporangium
#1
Damayanti Tammana, Trinadh Venkata Satish Tammana
Tubulin polymerization promoting proteins (TPPPs) belong to a family of neomorphic moon lighting proteins, involved in various physiological and pathological conditions. In physiological conditions, TPPPs play an important role in microtubule dynamics regulating mitotic spindle assembly and in turn cell proliferation. In pathological situations, TPPPs interact with α-synuclein and β-amyloid and promote their aggregation leading to Parkinson's disease and multiple system atrophy. Orthologs of TPPP family proteins were identified in ciliary proteomes from various organisms including Chlamydomonas but their role in ciliogenesis was not known...
2017: PloS One
https://www.readbyqxmd.com/read/28928732/facile-affinity-maturation-of-antibody-variable-domains-using-natural-diversity-mutagenesis
#2
Kathryn E Tiller, Ratul Chowdhury, Tong Li, Seth D Ludwig, Sabyasachi Sen, Costas D Maranas, Peter M Tessier
The identification of mutations that enhance antibody affinity while maintaining high antibody specificity and stability is a time-consuming and laborious process. Here, we report an efficient methodology for systematically and rapidly enhancing the affinity of antibody variable domains while maximizing specificity and stability using novel synthetic antibody libraries. Our approach first uses computational and experimental alanine scanning mutagenesis to identify sites in the complementarity-determining regions (CDRs) that are permissive to mutagenesis while maintaining antigen binding...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28927576/loss-of-microrna-7-regulation-leads-to-%C3%AE-synuclein-accumulation-and-dopaminergic-neuronal-loss-in%C3%A2-vivo
#3
Kirsty J McMillan, Tracey K Murray, Nora Bengoa-Vergniory, Oscar Cordero-Llana, Jane Cooper, Amy Buckley, Richard Wade-Martins, James B Uney, Michael J O'Neill, Liang F Wong, Maeve A Caldwell
Abnormal alpha-synuclein (α-synuclein) expression and aggregation is a key characteristic of Parkinson's disease (PD). However, the exact mechanism(s) linking α-synuclein to the other central feature of PD, dopaminergic neuron loss, remains unclear. Therefore, improved cell and in vivo models are needed to investigate the role of α-synuclein in dopaminergic neuron loss. MicroRNA-7 (miR-7) regulates α-synuclein expression by binding to the 3' UTR of the Synuclein Alpha Non A4 Component of Amyloid Precursor (SNCA) gene and inhibiting its translation...
August 31, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28924920/age-dependent-alpha-synuclein-accumulation-and-phosphorylation-in-the-enteric-nervous-system-in-a-transgenic-mouse-model-of-parkinson-s-disease
#4
Chong-Bin Zhong, Qian-Qian Chen, Caroline Haikal, Wen Li, Alexander Svanbergsson, Meike Diepenbroek, Jia-Yi Li
The enteric nervous system (ENS) controls the function of the gastrointestinal tract and has been implicated in various diseases, including Parkinson's disease (PD). PD is a neurodegenerative disease with Lewy bodies (LBs) and Lewy neurites (LNs) as the main pathological features. In addition to the typical motor symptoms in PD, attention has been drawn to non-motor symptoms, such as constipation, implying dysfunction of the ENS. In the present study, we characterized the age-dependent morphological alterations and aggregation of α-synuclein (α-syn), the primary protein component in LBs and LNs, in the ENS in an α-syn transgenic mouse model...
September 18, 2017: Neuroscience Bulletin
https://www.readbyqxmd.com/read/28923922/trkb-neurotrophic-activities-are-blocked-by-%C3%AE-synuclein-triggering-dopaminergic-cell-death-in-parkinson-s-disease
#5
Seong Su Kang, Zhentao Zhang, Xia Liu, Fredric P Manfredsson, Matthew J Benskey, Xuebing Cao, Jun Xu, Yi E Sun, Keqiang Ye
BDNF/TrkB neurotrophic signaling is essential for dopaminergic neuronal survival, and the activities are reduced in the substantial nigra (SN) of Parkinson's disease (PD). However, whether α-Syn (alpha-synuclein) aggregation, a hallmark in the remaining SN neurons in PD, accounts for the neurotrophic inhibition remains elusive. Here we show that α-Syn selectively interacts with TrkB receptors and inhibits BDNF/TrkB signaling, leading to dopaminergic neuronal death. α-Syn binds to the kinase domain on TrkB, which is negatively regulated by BDNF or Fyn tyrosine kinase...
September 18, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28922400/protein-folding-misfolding-and-aggregation-the-importance-of-two-electron-stabilizing-interactions
#6
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/28920936/dopamine-induces-soluble-%C3%AE-synuclein-oligomers-and-nigrostriatal-degeneration
#7
Danielle E Mor, Elpida Tsika, Joseph R Mazzulli, Neal S Gould, Hanna Kim, Malcolm J Daniels, Shachee Doshi, Preetika Gupta, Jennifer L Grossman, Victor X Tan, Robert G Kalb, Kim A Caldwell, Guy A Caldwell, John H Wolfe, Harry Ischiropoulos
Parkinson's disease (PD) is defined by the loss of dopaminergic neurons in the substantia nigra and the formation of Lewy body inclusions containing aggregated α-synuclein. Efforts to explain dopamine neuron vulnerability are hindered by the lack of dopaminergic cell death in α-synuclein transgenic mice. To address this, we manipulated both dopamine levels and α-synuclein expression. Nigrally targeted expression of mutant tyrosine hydroxylase with enhanced catalytic activity increased dopamine levels without damaging neurons in non-transgenic mice...
September 18, 2017: Nature Neuroscience
https://www.readbyqxmd.com/read/28918091/opposed-effects-of-dityrosine-formation-in-soluble-and-aggregated-%C3%AE-synuclein-on-fibril-growth
#8
Michael M Wördehoff, Hamed Shaykhalishahi, Luca Groß, Lothar Gremer, Matthias Stoldt, Alexander K Buell, Dieter Willbold, Wolfgang Hoyer
Parkinson's disease (PD) is the second most common neurodegenerative disease. It is characterized by aggregation of the protein α-synuclein (α-syn) in Lewy bodies, mitochondrial dysfunction, and increased oxidative stress in the substantia nigra. Oxidative stress leads to several modifications of biomolecules including dityrosine (DiY)-crosslinking in proteins, which has recently been detected in α-syn in Lewy bodies from PD patients. Here we report that α-syn is highly susceptible to UV-induced DiY formation...
September 13, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28914525/two-distinct-polymorphic-folding-states-of-self-assembly-of-the-non-amyloid-%C3%AE-component-differ-in-the-arrangement-of-the-residues
#9
Maya Pollock-Gagolashvili, Yifat Miller
Parkinson's disease is a degenerative disorder of the central nerves system. It is characterized by presence of Lew bodies (LBs), in which the main components of the LBs are α-synuclein (AS) aggregates. The central domain of AS, known as the "non-amyloid β component" (NAC) is responsible for the aggregation properties of AS. It is proposed that AS fibrillar structure is a well-packed cross-β structure of the NAC domains, while the N- and C-termini are disordered. Therefore, the study of the self-assembly of NAC domains are crucial in order to understand the molecular mechanisms of AS aggregation...
September 15, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28913005/chaperone-based-therapies-for-disease-modification-in-parkinson-s-disease
#10
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/28905328/lessons-learned-from-protein-aggregation-toward-technological-and-biomedical-applications
#11
REVIEW
César L Avila, Silvina Chaves, Sergio B Socias, Esteban Vera-Pingitore, Florencia González-Lizárraga, Cecilia Vera, Diego Ploper, Rosana Chehín
The close relationship between protein aggregation and neurodegenerative diseases has been the driving force behind the renewed interest in a field where biophysics, neurobiology and nanotechnology converge in the study of the aggregate state. On one hand, knowledge of the molecular principles that govern the processes of protein aggregation has a direct impact on the design of new drugs for high-incidence pathologies that currently can only be treated palliatively. On the other hand, exploiting the benefits of protein aggregation in the design of new nanomaterials could have a strong impact on biotechnology...
September 13, 2017: Biophysical Reviews
https://www.readbyqxmd.com/read/28903781/transmission-of-%C3%AE-synuclein-containing-erythrocyte-derived-extracellular-vesicles-across-the-blood-brain-barrier-via-adsorptive-mediated-transcytosis-another-mechanism-for-initiation-and-progression-of-parkinson-s-disease
#12
Junichi Matsumoto, Tessandra Stewart, Lifu Sheng, Na Li, Kristin Bullock, Ning Song, Min Shi, William A Banks, Jing Zhang
Parkinson's disease (PD) pathophysiology develops in part from the formation, transmission, and aggregation of toxic species of the protein α-synuclein (α-syn). Recent evidence suggests that extracellular vesicles (EVs) may play a vital role in the transport of toxic α-syn between brain regions. Moreover, increasing evidence has highlighted the participation of peripheral molecules, particularly inflammatory species, which may influence or exacerbate the development of PD-related changes to the central nervous system (CNS), although detailed characterization of these species remains to be completed...
September 13, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28900170/protein-arginylation-targets-alpha-synuclein-facilitates-normal-brain-health-and-prevents-neurodegeneration
#13
Junling Wang, Xuemei Han, Nicolae Adrian Leu, Stephanie Sterling, Satoshi Kurosaka, Marie Fina, Virginia M Lee, Dawei W Dong, John R Yates, Anna Kashina
Alpha synuclein (α-syn) is a central player in neurodegeneration, but the mechanisms triggering its pathology are not fully understood. Here we found that α-syn is a highly efficient substrate for arginyltransferase ATE1 and is arginylated in vivo by a novel mid-chain mechanism that targets the acidic side chains of E46 and E83. Lack of arginylation leads to increased α-syn aggregation and causes the formation of larger pathological aggregates in neurons, accompanied by impairments in its ability to be cleared via normal degradation pathways...
September 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28900007/e46k-%C3%AE-synuclein-pathological-mutation-causes-cell-autonomous-toxicity-without-altering-protein-turnover-or-aggregation
#14
Ignacio Íñigo-Marco, Miguel Valencia, Laura Larrea, Ricardo Bugallo, Mikel Martínez-Goikoetxea, Iker Zuriguel, Montserrat Arrasate
α-Synuclein (aSyn) is the main driver of neurodegenerative diseases known as "synucleinopathies," but the mechanisms underlying this toxicity remain poorly understood. To investigate aSyn toxic mechanisms, we have developed a primary neuronal model in which a longitudinal survival analysis can be performed by following the overexpression of fluorescently tagged WT or pathologically mutant aSyn constructs. Most aSyn mutations linked to neurodegenerative disease hindered neuronal survival in this model; of these mutations, the E46K mutation proved to be the most toxic...
September 12, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28900002/modeling-parkinson-s-disease-pathology-by-combination-of-fibril-seeds-and-%C3%AE-synuclein-overexpression-in-the-rat-brain
#15
Poonam Thakur, Ludivine S Breger, Martin Lundblad, Oi Wan Wan, Bengt Mattsson, Kelvin C Luk, Virginia M Y Lee, John Q Trojanowski, Anders Björklund
Although a causative role of α-synuclein (α-syn) is well established in Parkinson's disease pathogenesis, available animal models of synucleinopathy do not replicate the full range of cellular and behavioral changes characteristic of the human disease. This study was designed to generate a more faithful model of Parkinson's disease by injecting human α-syn fibril seeds into the rat substantia nigra (SN), in combination with adenoassociated virus (AAV)-mediated overexpression of human α-syn, at levels that, by themselves, are unable to induce acute dopamine (DA) neurodegeneration...
September 12, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28882310/studying-tau-protein-propagation-and-pathology-in-the-mouse-brain-using-adeno-associated-viruses
#16
Susanne Wegmann, Rachel E Bennett, Ana S Amaral, Bradley T Hyman
The progressive spread of pathological brain lesions containing aggregated tau protein is a hallmark of Alzheimer's disease and other neurodegenerative diseases. In AD, this process follows a distinct pattern along neuronal connections from the entorhinal cortex to hippocampal areas and further on through the limbic system. In other tauopathies, the spread of tau appears less hierarchical throughout the brain, and also nonpathological tau is reported to cross-synaptic connections in the brain. To be able to study the process of cell-to-cell transport of tau and the associated neurotoxicity in the brain in vivo, adeno-associated virus-mediated expression of tau can be used to express different forms of tau in distinct brain areas in rodent models...
2017: Methods in Cell Biology
https://www.readbyqxmd.com/read/28880418/diagnostic-utility-of-cerebrospinal-fluid-%C3%AE-synuclein-in-parkinson-s-disease-a-systematic-review-and-meta-analysis
#17
Paolo Eusebi, David Giannandrea, Leonardo Biscetti, Iosief Abraha, Davide Chiasserini, Massimiliano Orso, Paolo Calabresi, Lucilla Parnetti
BACKGROUND: The accumulation of misfolded α-synuclein aggregates is associated with PD. However, the diagnostic value of the α-synuclein levels in CSF is still under investigation. METHODS: A comprehensive search of the literature was performed, yielding 34 studies eligible for meta-analysis. We included studies that reported data on CSF total, oligomeric and phosphorylated α-synuclein in patients with PD and healthy participants, neurological controls, or other parkinsonisms...
September 7, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28874699/metal-concentrations-and-distributions-in-the-human-olfactory-bulb-in-parkinson-s-disease
#18
Bronwen Gardner, Birger V Dieriks, Steve Cameron, Lakshini H S Mendis, Clinton Turner, Richard L M Faull, Maurice A Curtis
In Parkinson's disease (PD), the olfactory bulb is typically the first region in the body to accumulate alpha-synuclein aggregates. This pathology is linked to decreased olfactory ability, which becomes apparent before any motor symptoms occur, and may be due to a local metal imbalance. Metal concentrations were investigated in post-mortem olfactory bulbs and tracts from 17 human subjects. Iron (p < 0.05) and sodium (p < 0.01) concentrations were elevated in the PD olfactory bulb. Combining laser ablation inductively coupled plasma mass spectrometry and immunohistochemistry, iron and copper were evident at very low levels in regions of alpha-synuclein aggregation...
September 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28872299/comparison-of-%C3%AE-synuclein-fibril-inhibition-by-four-different-amyloid-inhibitors
#19
Narendra Nath Jha, Rakesh Kumar, Rajlaxmi Panigrahi, Ambuja Navalkar, Dhiman Ghosh, Shruti Sahay, Mrityunjoy Mondal, Ashutosh Kumar, Samir K Maji
Aggregation of α-synuclein (α-Syn) into toxic oligomers and fibrils leads to Parkinson's disease (PD) pathogenesis. Molecules that can inhibit the fibrillization and oligomerization of α-Syn have potential therapeutic value. Here, we studied four selective amyloid inhibitors: Dopamine (Dopa), Amphotericin-B (Amph), Epigallocatechingallate (EGCG) and Quinacrinedihydrochloride (Quin) for their effect on oligomerization, fibrillization and preformed fibrils of α-Syn. The aggregation kinetics of α-Syn using ThT fluorescence and conformational transition by circular dichroism (CD) in the presence and absence of these four compounds suggest that, except Quin, remaining three molecules inhibit α-Syn aggregation in concentration dependent manner...
September 5, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28870519/sigma-1-receptor-knockout-increases-%C3%AE-synuclein-aggregation-and-phosphorylation-with-loss-of-dopaminergic-neurons-in-substantia-nigra
#20
Juan Hong, Ling Wang, Tingting Zhang, Baofeng Zhang, Ling Chen
Sigma-1 receptor (σ1R) is expressed in dopaminergic neurons of substantia nigra. Here, we show that σ1R knockout (σ1R(-/-)) mice, at age 6-12 months, appeared with age-related loss of dopaminergic neurons and decline of motor coordination. Levels of α-synuclein (αSyn) oligomers and fibrillar αSyn in substantia nigra of σ1R(-/-) mice were age-dependently increased without the changes in αSyn monomers. The phosphorylation of αSyn monomers or oligomers in dopaminergic neurons was enhanced in σ1R(-/-) mice...
August 10, 2017: Neurobiology of Aging
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