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synuclein and aggregation

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https://www.readbyqxmd.com/read/29458128/aggregation-prone-regions-in-hypk-help-it-to-form-sequestration-complex-for-toxic-protein-aggregates
#1
Debasish Kumar Ghosh, Ajit Roy, Akash Ranjan
Protein aggregates result from altered structural conformations and they can perturb cellular homeostasis. Prevention mechanisms, which function against protein aggregation by modulatory processes, are diverse and redundant. In this study, we have characterized Huntingtin interacting protein K (HYPK) as a global aggregation-regulatory protein. We report the mechanistic details of how HYPK's aggregation-prone regions allow it to sense and prevent other toxic protein's aggregation by forming unique annular-shaped sequestration complexes...
February 16, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29451381/from-a-highly-disordered-to-a-metastable-state-uncovering-insights-of-%C3%AE-synuclein
#2
Yoann Cote, Patrice Delarue, Harold Abraham Scheraga, Patrick Senet, Gia G Maisuradze
α-synuclein (αS) is a major constituent of Lewy bodies, the insoluble aggregates that are the hallmark of one of the most prevalent neurodegenerative disorders - Parkinson's disease (PD). The vast majority of experiments in vitro and in vivo provide extensive evidence that a disordered monomeric form is the predominant state of αS in water solution, and it undergoes a large-scale disorder-to-helix transition upon binding to vesicles of different types. Recently, another form, tetrameric, of αS with a stable helical structure was identified experimentally...
February 16, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29441013/%C3%AE-synuclein-aggregated-with-tau-and-%C3%AE-amyloid-in-human-platelets-from-healthy-subjects-correlation-with-physical-exercise
#3
Simona Daniele, Deborah Pietrobono, Jonathan Fusi, Annalisa Lo Gerfo, Eugenio Cerri, Lucia Chico, Caterina Iofrida, Lucia Petrozzi, Filippo Baldacci, Chiara Giacomelli, Fabio Galetta, Gabriele Siciliano, Ubaldo Bonuccelli, Maria L Trincavelli, Ferdinando Franzoni, Claudia Martini
The loss of protein homeostasis that has been associated with aging leads to altered levels and conformational instability of proteins, which tend to form toxic aggregates. In particular, brain aging presents characteristic patterns of misfolded oligomers, primarily constituted of β-amyloid (Aβ), tau, and α-synuclein (α-syn), which can accumulate in neuronal membranes or extracellular compartments. Such aging-related proteins can also reach peripheral compartments, thus suggesting the possibility to monitor their accumulation in more accessible fluids...
2018: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/29434298/loss-of-autophagy-in-dopaminergic-neurons-causes-lewy-pathology-and-motor-dysfunction-in-aged-mice
#4
Shigeto Sato, Toshiki Uchihara, Takahiro Fukuda, Sachiko Noda, Hiromi Kondo, Shinji Saiki, Masaaki Komatsu, Yasuo Uchiyama, Keiji Tanaka, Nobutaka Hattori
Inactivation of constitutive autophagy results in the formation of cytoplasmic inclusions in neurons, but the relationship between impaired autophagy and Lewy bodies (LBs) as well as the in vivo process of formation remains unknown. Synuclein, a component of LBs, is the defining characteristic of Parkinson's disease (PD). Here, we characterize dopamine (DA) neuron-specific autophagy-deficient mice and provide in vivo evidence for LB formation. Synuclein deposition is preceded by p62 and resulted in the formation of inclusions containing synuclein and p62...
February 12, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29432756/region-and-cell-specific-aneuploidy-in-brain-aging-and-neurodegeneration
#5
REVIEW
C E Shepherd, Y Yang, G M Halliday
Variations in genomic DNA content, or aneuploidy, are a well-recognized feature of normal human brain development. Whether changes in the levels of aneuploidy are a factor in Alzheimer's disease (AD) is less clear, as the data reported to date vary substantially in the levels of aneuploidy detected (0.7-11.5%), possibly due to methodological limitations, but also influenced by individual, regional and cellular heterogeneity as well as variations in cell subtypes. These issues have not been adequately addressed to date...
February 9, 2018: Neuroscience
https://www.readbyqxmd.com/read/29422109/lack-of-pathogenic-potential-of-peripheral-%C3%AE-synuclein-aggregates-from-parkinson-s-disease-patients
#6
Ariadna Recasens, Iria Carballo-Carbajal, Annabelle Parent, Jordi Bové, Ellen Gelpi, Eduardo Tolosa, Miquel Vila
In Parkinson's disease (PD) there is widespread accumulation in the brain of abnormal α-synuclein aggregates forming intraneuronal Lewy bodies (LB). It is now well established that LB-type α-synuclein aggregates also occur in the peripheral autonomic nervous system in PD, from where it has been speculated they may progressively spread to the central nervous system through synaptically-connected brain networks and reach the substantia nigra to trigger herein dopaminergic dysfunction/degeneration and subsequent parkinsonism...
February 8, 2018: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/29418019/new-developments-in-genetic-rat-models-of-parkinson-s-disease
#7
REVIEW
Rose B Creed, Matthew S Goldberg
Preclinical research on Parkinson's disease has relied heavily on mouse and rat animal models. Initially, PD animal models were generated primarily by chemical neurotoxins that induce acute loss of dopaminergic neurons in the substantia nigra. On the discovery of genetic mutations causally linked to PD, mice were used more than rats to generate laboratory animals bearing PD-linked mutations because mutagenesis was more difficult in rats. Recent advances in technology for mammalian genome engineering and optimization of viral expression vectors have increased the use of genetic rat models of PD...
February 8, 2018: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/29417650/a-peptide-display-protein-scaffold-to-facilitate-single-molecule-force-studies-of-aggregation-prone-peptides
#8
Ciaran P A Doherty, Lydia M Young, Theodoros K Karamanos, Hugh I Smith, Matthew P Jackson, Sheena E Radford, David J Brockwell
Protein aggregation is linked with the onset of several neurodegenerative disorders, including Parkinson's disease (PD), which is associated with the aggregation of α-synuclein (αSyn). The structural mechanistic details of protein aggregation, including the nature of the earliest protein:protein interactions, remain elusive. In this study we have used single molecule force spectroscopy (SMFS) to probe the first dimerisation events of the central aggregation-prone region of αSyn (residues 71-82) that may initiate aggregation...
February 8, 2018: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/29414379/prion-like-seeding-and-nucleation-of-intracellular-amyloid-%C3%AE
#9
Tomas T Olsson, Oxana Klementieva, Gunnar K Gouras
Alzheimer's disease (AD) brain tissue can act as a seed to accelerate aggregation of amyloid-β (Aβ) into plaques in AD transgenic mice. Aβ seeds have been hypothesized to accelerate plaque formation in a prion-like manner of templated seeding and intercellular propagation. However, the structure(s) and location(s) of the Aβ seeds remain unknown. Moreover, in contrast to tau and α-synuclein, an in vitro system with prion-like Aβ has not been reported. Here we treat human APP expressing N2a cells with AD transgenic mouse brain extracts to induce inclusions of Aβ in a subset of cells...
January 29, 2018: Neurobiology of Disease
https://www.readbyqxmd.com/read/29414104/acrolein-mediated-neuronal-cell-death-and-alpha-synuclein-aggregation-implications-for-parkinson-s-disease
#10
Abeje Ambaw, Lingxing Zheng, Mitali A Tambe, Katherine E Strathearn, Glen Acosta, Scott A Hubers, Fang Liu, Seth A Herr, Jonathan Tang, Alan Truong, Elwood Walls, Amber Pond, Jean-Christophe Rochet, Riyi Shi
Growing evidence suggests that oxidative stress plays a critical role in neuronal destruction characteristic of Parkinson's disease (PD). However, the molecular mechanisms of oxidative stress-mediated dopaminergic cell death are far from clear. In the current investigation, we tested the hypothesis that acrolein, an oxidative stress and lipid peroxidation (LPO) product, is a key factor in the pathogenesis of PD. Using a combination of in vitro, in vivo, and cell free models, coupled with anatomical, functional, and behavioral examination, we found that acrolein was elevated in 6-OHDA-injected rats, and behavioral deficits associated with 6-OHDA could be mitigated by the application of the acrolein scavenger hydralazine, and mimicked by injection of acrolein in healthy rats...
January 29, 2018: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/29414102/drp-1-dependent-mitochondrial-fragmentation-and-protective-autophagy-in-dopaminergic-sh-sy5y-cells-overexpressing-alpha-synuclein
#11
Jimena Hebe Martinez, Agustina Alaimo, Roxana Mayra Gorojod, Soledad Porte Alcon, Federico Fuentes, Federico Coluccio Leskow, Mónica Lidia Kotler
Parkinson's disease is a neurodegenerative movement disorder caused by the loss of dopaminergic neurons from substantia nigra. It is characterized by the accumulation of aggregated α-synuclein as the major component of the Lewy bodies. Additional common features of this disease are the mitochondrial dysfunction and the activation/inhibition of autophagy both events associated to the intracellular accumulation of α-synuclein. The mechanism by which these events contribute to neural degeneration remains unknown...
January 27, 2018: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/29411106/release-and-uptake-of-pathologic-alpha-synuclein
#12
REVIEW
Veselin Grozdanov, Karin M Danzer
Parkinson's disease (PD) is a chronic progressive neurodegenerative disease, which is characterized by severe loss of dopaminergic neurons and formation of Lewy bodies, which are rich in aggregated alpha-synuclein (α-syn). Two decades of intensive research have compiled a massive body of evidence that aggregation of α-syn is a critical process in PD and other synucleinopathies. The dissemination of Lewy body pathology throughout the central nervous system strongly suggests a cell-to-cell transmission of α-syn...
February 6, 2018: Cell and Tissue Research
https://www.readbyqxmd.com/read/29410282/osmotic-stress-induced-toxicity-exacerbates-parkinson-s-associated-effects-via-dysregulation-of-autophagy-in-transgenic-c-elegans-model
#13
Pooja Jadiya, Snober S Mir, Aamir Nazir
The accumulation of aggregate-prone proteins is a major representative of many neurological disorders, including Parkinson's disease (PD) wherein the cellular clearance mechanisms, such as the ubiquitin-proteasome and autophagy pathways are impaired. PD, known to be associated with multiple genetic and environmental factors, is characterized by the aggregation of α-synuclein protein and loss of dopaminergic neurons in midbrain. This disease is also associated with other cardiovascular ailments. Herein, we report our findings from studies on the effect of hyper and hypo-osmotic induced toxicity representing hyper and hypotensive condition as an extrinsic epigenetic factor towards modulation of Parkinsonism, using a genetic model Caenorhabditis elegans (C...
February 2, 2018: Cellular Signalling
https://www.readbyqxmd.com/read/29409956/the-interaction-between-calcineurin-and-%C3%AE-synuclein-is-regulated-by-calcium-and-calmodulin
#14
Xiaoyu Shi, Yue Sun, Ping Wang, Lingling Gu, Lu Wang, Huan Yang, Qun Wei, Zhimei Li, Jing Luo
Calcineurin (CN) is a protein phosphatase and widely distributed in eukaryotes, with an extremely high level of expression in mammalian brain. Alpha-synuclein (α-syn) is a small soluble protein expressed primarily at presynaptic terminals in the central nervous system. In our present study, we explored the interactions between CN and α-syn in vitro. Based on the data from microscale thermophoresis, GST pull-down assays, and co-immunoprecipitation, we found that CN binds α-syn. Furthermore, this interaction is mediated by calcium/calmodulin (Ca2+/CaM) signaling...
January 30, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29408361/binding-of-alpha-synuclein-to-partially-oxidized-glyceraldehyde-3-phosphate-dehydrogenase-induces-subsequent-inactivation-of-the-enzyme
#15
Kseniya Barinova, Evgeniya Khomyakova, Pavel Semenyuk, Elena Schmalhausen, Vladimir Muronetz
According to literature data, the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) co-localizes with alpha-synuclein in Lewy bodies in Parkinson's disease, which suggests the involvement of this protein in the development of synucleinopathies. The goal of the present work was to investigate the direct interaction between alpha-synuclein and GAPDH and to evaluate possible influence of this interaction on the catalytic properties of GAPDH. Molecular dynamic simulations predicted the binding of alpha-synuclein to the positively charged groove comprising NAD+-binding pocket of GAPDH...
February 3, 2018: Archives of Biochemistry and Biophysics
https://www.readbyqxmd.com/read/29400127/glucocerebrosidase-and-parkinson-disease-molecular-clinical-and-therapeutic-implications
#16
Roberta Balestrino, Anthony H V Schapira
Parkinson disease (PD) is a complex neurodegenerative disease characterised by multiple motor and non-motor symptoms. In the last 20 years, more than 20 genes have been identified as causes of parkinsonism. Following the observation of higher risk of PD in patients affected by Gaucher disease, a lysosomal disorder caused by mutations in the glucocerebrosidase (GBA) gene, it was discovered that mutations in this gene constitute the single largest risk factor for development of idiopathic PD. Patients with PD and GBA mutations are clinically indistinguishable from patients with idiopathic PD, although some characteristics emerge depending on the specific mutation, such as slightly earlier onset...
February 1, 2018: Neuroscientist: a Review Journal Bringing Neurobiology, Neurology and Psychiatry
https://www.readbyqxmd.com/read/29390878/neuroprotective-effects-of-betulin-in-pharmacological-and-transgenic-caenorhabditis-elegans-models-of-parkinson-s-disease
#17
Chia-Wen Tsai, Rong-Tzong Tsai, Shih-Ping Liu, Chang-Shi Chen, Min-Chen Tsai, Shao-Hsuan Chien, Huey-Shan Hung, Shinn-Zong Lin, Woei-Cherng Shyu, Ru-Huei Fu
Parkinson's disease (PD) is the second most common degenerative disorder of the central nervous system in the elderly. It is characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta, as well as by motor dysfunction. Although the causes of PD are not well understood, aggregation of α-synuclein (α-syn) in neurons contributes to this disease. Current therapeutics for PD provides satisfactory symptom relief but not a cure. Treatment strategies include attempts to identify new drugs that will prevent or arrest the progressive course of PD by correcting disease-specific pathogenic process...
December 2017: Cell Transplantation
https://www.readbyqxmd.com/read/29382893/molecular-role-of-ca2-and-hard-divalent-metal-cations-on-accelerated-fibrillation-and-interfibrillar-aggregation-of-%C3%AE-synuclein
#18
Jong Yoon Han, Tae Su Choi, Hugh I Kim
α-Synuclein (αSyn) is an intrinsically disordered protein, the aggregation of which is highly related to the pathology of diverse α-synucleinopathies. Various hard divalent metal cations have been shown to affect αSyn aggregation. Especially, Ca2+ is suggested to be a crucial ion due to its physiological relevance to α-synucleinopathies. However, the molecular origin of αSyn aggregation mediated by the metal ions is not fully elucidated. In this study, we revealed that hard divalent metal ions had almost identical influences on αSyn aggregation...
January 30, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29382725/the-small-heat-shock-protein-hsp27-binds-%C3%AE-synuclein-fibrils-preventing-elongation-and-cytotoxicity
#19
Dezerae Cox, Daniel R Whiten, James Brown, Mathew H Horrocks, Rebecca San Gil, Christopher M Dobson, David Klenerman, Antoine M van Oijen, Heath Ecroyd
Proteostasis, or protein homeostasis, encompasses the maintenance of the conformational and functional integrity of the proteome and involves an integrated network of cellular pathways. Molecular chaperones, such as the small heat shock proteins (sHsps), are a key element of the proteostasis network that have crucial roles in inhibiting the aggregation of misfolded proteins. Failure of the proteostasis network can lead to the accumulation of misfolded proteins into intra- and extracellular deposits. Deposits containing fibrillar forms of α- synuclein (α-syn) are characteristic of neurodegenerative disorders including Parkinson's disease and dementia with Lewy bodies...
January 30, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29378654/exceptional-in-vivo-catabolism-of-neurodegeneration-related-aggregates
#20
Zsolt Datki, Zita Olah, Tibor Hortobagyi, Lilla Macsai, Katalin Zsuga, Livia Fulop, Zsolt Bozso, Bence Galik, Eva Acs, Angela Foldi, Amanda Szarvas, Janos Kalman
Neurodegenerative diseases are linked to a systemic enzyme resistance of toxic aggregated molecules and their pathological consequences. This paper presents a unique phenomenon that Philodina acuticornis, a bdelloid rotifer, is able to catabolize different types of neurotoxic peptide and protein aggregates (such as beta-amyloids /Aβ/, alpha-synuclein, and prion) without suffering any damage. P. acuticornis is capable of using these aggregates as an exclusive energy source (i.e., as 'food', identified in the digestive system and body) in a hermetically isolated microdrop environment, increasing their survival...
January 29, 2018: Acta Neuropathologica Communications
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