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alpha synuclein and aggregation

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https://www.readbyqxmd.com/read/29341898/induction-of-alpha-synuclein-pathology-in-the-enteric-nervous-system-of-the-rat-and-non-human-primate-results-in-gastrointestinal-dysmotility-and-transient-cns-pathology
#1
Fredric P Manfredsson, Kelvin C Luk, Matthew J Benskey, Aysegul Guezer, Joanna Garcia, Nathan C Kuhn, Ivette M Sandoval, Joseph R Patterson, Alana O'Mara, Reid Yonkers, Jeffrey H Kordower
Alpha-Synuclein (α-syn) is by far the most highly vetted pathogenic and therapeutic target in Parkinson's disease. Aggregated α-syn is present in sporadic Parkinson's disease, both in the central nervous system (CNS) and peripheral nervous system (PNS). The enteric division of the PNS is of particular interest because 1) gastric dysfunction is a key clinical manifestation of Parkinson's disease, and 2) Lewy pathology in myenteric and submucosal neurons of the enteric nervous system (ENS) has been referred to as stage zero in the Braak pathological staging of Parkinson's disease...
January 13, 2018: Neurobiology of Disease
https://www.readbyqxmd.com/read/29305919/pathological-role-of-lipid-interaction-with-%C3%AE-synuclein-in-parkinson-s-disease
#2
REVIEW
Mari Suzuki, Kazunori Sango, Keiji Wada, Yoshitaka Nagai
Alpha-synuclein (αSyn) plays a central role in the pathogenesis of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In sporadic PD and DLB, normally harmless αSyn proteins without any mutations might gain toxic functions by unknown mechanisms. Thus, it is important to elucidate the factors promoting the toxic conversion of αSyn, towards understanding the pathogenesis of and developing disease-modifying therapies for PD and DLB. Accumulating biophysical and biochemical studies have demonstrated that αSyn interacts with lipid membrane, and the interaction influences αSyn oligomerization and aggregation...
January 3, 2018: Neurochemistry International
https://www.readbyqxmd.com/read/29305061/a-refined-concept-%C3%AE-synuclein-dysregulation-disease
#3
REVIEW
Hideki Mochizuki, Chi-Jing Choong, Eliezer Masliah
α-synuclein (αSyn) still remains a mysterious protein even two decades after SNCA encoding it was identified as the first causative gene of familial Parkinson's disease (PD). Accumulation of αSyn causes α-synucleinopathies including PD, dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Recent advances in therapeutic approaches offer new antibody-, vaccine-, antisense-oligonucleotide- and small molecule-based options to reduce αSyn protein levels and aggregates in patient's brain. Gathering research information of other neurological disease particularly Alzheimer's disease, recent disappointment of an experimental amyloid plaques busting antibody in clinical trials underscores the difficulty of treating people who show even mild dementia as damage in their brain may already be too extensive...
January 2, 2018: Neurochemistry International
https://www.readbyqxmd.com/read/29278715/accumulation-of-beta-synuclein-in-cortical-neurons-is-associated-with-autophagy-attenuation-in-the-brains-of-dementia-with-lewy-body-patients
#4
Tracey Evans, Wai Ling Kok, Katrina Cowan, Megan Hefford, Oleg Anichtchik
Dementia with Lewy bodies (DLB) is the second most prevalent neurodegenerative dementia, where an accumulation of aggregated fibrillar alpha-synuclein in neurons of limbic and forebrain regions of the brain leads to visual hallucination, cognitive impairment of a fluctuating nature and extrapyramidal motor disturbances. Beta-synuclein counteracts aggregation of alpha-synuclein in vitro and in animal models, however it is not clear whether this effect occurs in human Lewy body dementia (LBD) diseases. Here we examine expression of alpha-, beta-synuclein and autophagy markers in the frontal cortex (BA9) and occipital cortex (BA18-19) of patients with neuropathologically confirmed DLB/LBD and age-matched controls...
December 23, 2017: Brain Research
https://www.readbyqxmd.com/read/29276384/investigation-of-the-effects-of-carbon-based-nanomaterials-on-a53t-alpha-synuclein-aggregation-using-a-whole-cell-recombinant-biosensor
#5
Soheila Mohammadi, Maryam Nikkhah, Saman Hosseinkhani
The aggregation of alpha-synuclein (αS), natively unstructured presynaptic protein, is a crucial factor leading to the pathogenesis of Parkinson's disease (PD) and other related disorders. Recent studies have shown prefibrillar and oligomeric intermediates of αS as toxic to the cells. Herein, split-luciferase complementation assay is used to design a "signal-on" biosensor to monitor oligomerization of A53T αS inside the cells. Then, the effect of carbon-based nanomaterials, such as graphene quantum dots (GQDs) and graphene oxide quantum dots (GOQDs), on A53T αS oligomerization in vitro and in living cells is investigated...
2017: International Journal of Nanomedicine
https://www.readbyqxmd.com/read/29246724/toxic-properties-of-microsome-associated-alpha-synuclein-species-in-mouse-primary-neurons
#6
Emanuela Colla, Giulia Panattoni, Alessio Ricci, Caterina Rizzi, Lucia Rota, Nicola Carucci, Verdiana Valvano, Francesco Gobbo, Simona Capsoni, Michael K Lee, Antonino Cattaneo
α-synuclein (αS) is a small protein that self-aggregates into α-helical oligomer species and subsequently into larger insoluble amyloid fibrils that accumulate in intraneuronal inclusions during the development of Parkinson's disease. Toxicity of αS oligomers and fibrils has been long debated and more recent data are suggesting that both species can induce neurodegeneration. However while most of these data are based on differences in structure between oligomer and aggregates, often preassembled in vitro, the in vivo situation might be more complex and subcellular locations where αS species accumulate, rather than their conformation, might contribute to enhanced toxicity...
December 12, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/29227247/stress-induced-cdk5-activity-enhances-cytoprotective-basal-autophagy-in-drosophila-melanogaster-by-phosphorylating-acinus-at-serine437
#7
Nilay Nandi, Lauren K Tyra, Drew Stenesen, Helmut Krämer
Cdk5 is a post-mitotic kinase with complex roles in maintaining neuronal health. The various mechanisms by which Cdk5 inhibits and promotes neurodegeneration are still poorly understood. Here, we show that in Drosophila melanogaster Cdk5 regulates basal autophagy, a key mechanism suppressing neurodegeneration. In a targeted screen, Cdk5 genetically interacted with Acinus (Acn), a primarily nuclear protein, which promotes starvation-independent, basal autophagy. Loss of Cdk5, or its required cofactor p35, reduces S437-Acn phosphorylation, whereas Cdk5 gain-of-function increases pS437-Acn levels...
December 11, 2017: ELife
https://www.readbyqxmd.com/read/29217686/synaptic-regulator-%C3%AE-synuclein-in-dopaminergic-fibers-is-essentially-required-for-the-maintenance-of-subependymal-neural-stem-cells
#8
Ana Perez-Villalba, Mª Salomé Sirerol-Piquer, Germán Belenguer, Raúl Soriano-Cantón, Ana Belén Muñoz-Manchado, Javier Villadiego, Diana Alarcón-Arís, Federico N Soria, Benjamin Dehay, Erwan Bezard, Miquel Vila, Analía Bortolozzi, Juan José Toledo-Aral, Francisco Pérez-Sánchez, Isabel Fariñas
Synaptic protein α-synuclein (α-SYN) modulates neurotransmission in a complex and poorly understood manner and aggregates in the cytoplasm of degenerating neurons in Parkinson's disease. Here, we report that α-SYN present in dopaminergic nigral afferents is essential for the normal cycling and maintenance of neural stem cells (NSCs) in the brain subependymal zone of adult male and female mice. We also show that premature senescence of adult NSCs into non-neurogenic astrocytes in mice lacking α-SYN resembles the effects of dopaminergic fiber degeneration resulting from chronic exposure to MPTP or intranigral inoculation of aggregated toxic α-SYN...
December 6, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29214369/ginkgolide-k-promotes-the-clearance-of-a53t-mutation-alpha-synuclein-in-sh-sy5y-cells
#9
Wenbo Yu, Sheng Chen, Liang Cao, Jie Tang, Wei Xiao, Baoguo Xiao
Alpha-synuclein (α-syn) is associated to Parkinson's disease (PD). The aggregated form of α-syn has potential neurotoxicity. Thus, the clearance of α-syn aggregation is a plausible strategy to delay disease progression of PD. In our study, we found that the treatment of Ginkgolide B (GB) and Ginkgolide K (GK) reduced cell death, and enhanced cell proliferation in SH-SY5Y cells, which overexpressed A53T mutant α-syn. Surprisingly, GK, but not GB, promoted the clearance of A53T α-syn, which can be abolished by autophagy inhibitor 3-methyladenine, indicating that GK-induced autophagy intervened in the clearance of A53T α-syn...
December 6, 2017: Cell Biology and Toxicology
https://www.readbyqxmd.com/read/29198021/alpha-synuclein-aggregation-ubiquitin-proteasome-system-impairment-and-l-dopa-response-in-zinc-induced-parkinsonism-resemblance-to-sporadic-parkinson-s-disease
#10
Vinod Kumar, Deepali Singh, Brajesh Kumar Singh, Shweta Singh, Namrata Mittra, Rakesh Roshan Jha, Devendra Kumar Patel, Chetna Singh
Alpha-synuclein (α-synuclein) aggregation and impairment of the Ubiquitin proteasome system (UPS) are implicated in Parkinson's disease (PD) pathogenesis. While zinc (Zn) induces dopaminergic neurodegeneration resulting in PD phenotype, its effect on protein aggregation and UPS has not yet been deciphered. The current study investigated the role of α-synuclein aggregation and UPS in Zn-induced Parkinsonism. Additionally, levodopa (L-Dopa) response was assessed in Zn-induced Parkinsonian model to establish its closeness with idiopathic PD...
December 2, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/29189163/alpha-synuclein-proteotoxicity-and-parkinson-s-disease-search-for-neuroprotective-therapy
#11
Upasana Ganguly, Sankha Shubhra Chakrabarti, Upinder Kaur, Anwesha Mukherjee, Sasanka Chakrabarti
There is a growing body of evidence in animal and cell based models of Parkinson's disease (PD) to suggest that overexpression and / or abnormal accumulation and aggregation of α-synuclein can trigger neuronal death. This important role of α-synuclein in PD pathogenesis is supported by the fact that duplication, triplication and mutations of α-synuclein gene cause familial forms of PD. The overexpression and accumulation of α-synuclein within neurons may involve both transcriptional and post-transcriptional mechanisms including a decreased degradation of the protein through proteasomal or autophagic processes...
November 28, 2017: Current Neuropharmacology
https://www.readbyqxmd.com/read/29185072/in-vivo-models-of-alpha-synuclein-transmission-and-propagation
#12
REVIEW
Ariadna Recasens, Ayse Ulusoy, Philipp J Kahle, Donato A Di Monte, Benjamin Dehay
The abnormal accumulation of α-synuclein aggregates in neurons, nerve fibers, or glial cells is the hallmark of a group of neurodegenerative diseases known collectively as α-synucleinopathies. Clinical, neuropathological, and experimental evidence strongly suggests that α-synuclein plays a role not only as a trigger of pathological processes at disease inception, but also as a mediator of pathological spreading during disease progression. Specific properties of α-synuclein, such as its ability to pass from one neuron to another, its tendency to aggregate, and its potential to generate self-propagating species, have been described and elucidated in animal models and may contribute to the relentless exacerbation of Parkinson's disease pathology in patients...
November 29, 2017: Cell and Tissue Research
https://www.readbyqxmd.com/read/29180135/alpha-synuclein-transgenic-mice-h-%C3%AE-synl62-display-%C3%AE-syn-aggregation-and-a-dopaminergic-phenotype-reminiscent-of-parkinson-s-disease
#13
Silke Frahm, Valeria Melis, David Horsley, Janet E Rickard, Gernot Riedel, Paula Fadda, Maria Scherma, Charles R Harrington, Claude M Wischik, Franz Theuring, Karima Schwab
Alpha-Synuclein (α-Syn) accumulation is considered a major risk factor for the development of synucleinopathies such as Parkinson's disease (PD) and dementia with Lewy bodies. We have generated mice overexpressing full-length human α-Syn fused to a membrane-targeting signal sequence under the control of the mouse Thy1-promotor. Three separate lines (L56, L58 and L62) with similar gene expression levels, but considerably heightened protein accumulation in L58 and L62, were established. In L62, there was widespread labelling of α-Syn immunoreactivity in brain including spinal cord, basal forebrain, cortex and striatum...
February 26, 2018: Behavioural Brain Research
https://www.readbyqxmd.com/read/29150334/a-routinely-used-protein-staining-dye-acts-as-an-inhibitor-of-wild-type-and-mutant-alpha-synuclein-aggregation-and-modulator-of-neurotoxicity
#14
Nuzhat Ahsan, Ibrar Ahmed Siddique, Sarika Gupta, Avadhesha Surolia
Inhibition of amyloid formation along with modulation of toxicity employing small molecules is emerging as a potential therapeutic approach for protein misfolding disorders which includes Parkinson's disease, Alzheimer's disease and Multiple System Atrophy etc. Countless current interventional strategies for treating α-synucleinopathies consider using peptidic and non-peptidic inhibitors for arresting fibrillisation, disrupting existing fibrils and reducing associated toxicity. One group of molecules less exploited in this regard are triphenylmethane dyes...
October 12, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29143358/melatonin-improves-survival-and-respiratory-activity-of-yeast-cells-challenged-by-alpha-synuclein-and-menadione
#15
Mariana A Zampol, Mario H Barros
One of the hallmarks of Parkinson disease is α-synuclein aggregate deposition that leads to ER stress, Golgi fragmentation, and impaired energy metabolism with consequent redox imbalance. In the last decade, many studies have used Saccharomyces cerevisiae as a model in order to explore the intracellular consequences of α-synuclein overexpression. In this study we propose to evaluate the respiratory outcome of yeast cells expressing α-synuclein. Cell viability, or growth on selective media for respiratory activity was mainly affected in the α-synuclein expressing cells if they were also treated with menadione, which stimulates ROS production...
November 16, 2017: Yeast
https://www.readbyqxmd.com/read/29142509/using-an-nmr-metabolomics-approach-to-investigate-the-pathogenicity-of-amyloid-beta-and-alpha-synuclein
#16
M M Phelan, E Caamaño-Gutiérrez, M S Gant, R X Grosman, J Madine
Introduction: The pathogenicity at differing points along the aggregation pathway of many fibril-forming proteins associated with neurodegenerative diseases is unclear. Understanding the effect of different aggregation states of these proteins on cellular processes is essential to enhance understanding of diseases and provide future options for diagnosis and therapeutic intervention. Objectives: To establish a robust method to probe the metabolic changes of neuronal cells and use it to monitor cellular response to challenge with three amyloidogenic proteins associated with neurodegenerative diseases in different aggregation states...
2017: Metabolomics: Official Journal of the Metabolomic Society
https://www.readbyqxmd.com/read/29137980/interaction-of-alpha-synuclein-with-cytogaligin-a-protein-encoded-by-the-proapoptotic-gene-galig
#17
Saïd El Haddad, Amandine Serrano, Thierry Normand, Chloé Robin, Martine Dubois, Fabienne Brule-Morabito, Lucile Mollet, Stéphane Charpentier, Alain Legrand
GALIG, an internal gene to the human galectin-3 gene, encodes two distinct proteins, Mitogaligin and Cytogaligin through translation of a unique mRNA in two overlapping alternative reading frames. When overexpressed GALIG induces apoptosis. In cultured cells, Mitogaligin destabilizes mitochondria membranes through interaction with cardiolipin. Little is known regarding the role of Cytogaligin. This protein displays multiple subcellular localizations; cytosol, nucleus, and mitochondria. We illustrate here that Cytogaligin is also secreted in the extracellular medium...
November 11, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29130469/-heparan-sulphates-amyloidosis-and-neurodegeneration
#18
REVIEW
C Vera, J A Alvarez-Orozco, A Maiza, S Chantepie, R N Chehin, M O Ouidja, D Papy-Garcia
INTRODUCTION: A number of neurodegenerative disorders have been linked directly to the accumulation of amyloid fibres. These fibres are made up of proteins or peptides with altered structures and which join together in vivo in association with heparan sulphate-type polysaccharides. AIMS: To examine the most recent concepts in the biology of heparan sulphates and their role in the aggregation of the peptide Abeta, of tau protein, of alpha-synuclein and of prions...
November 16, 2017: Revista de Neurologia
https://www.readbyqxmd.com/read/29124503/urological-dysfunction-in-synucleinopathies-epidemiology-pathophysiology-and-management
#19
REVIEW
Ryuji Sakakibara, Fuyuki Tateno, Tatsuya Yamamoto, Tomoyuki Uchiyama, Tomonori Yamanishi
OBJECTIVE: Parkinson's disease (PD) and multiple system atrophy (MSA) are major neurogenerative diseases characterized pathologically by abnormal alpha-synuclein aggregation. PD and MSA are clinically characterized by motor disorder and bladder dysfunction (mainly urinary urgency and frequency, also called overactive bladder). However, few literatures are available concerning bladder dysfunction in PD or MSA. METHOD: A systematic review. RESULTS: The bladder dysfunction in MSA is more severe than that in PD for large post-void residual or urinary retention...
November 9, 2017: Clinical Autonomic Research: Official Journal of the Clinical Autonomic Research Society
https://www.readbyqxmd.com/read/29107086/age-dependent-elevations-of-oligomeric-and-phosphorylated-alpha-synuclein-synchronously-occurs-in-the-brain-and-gastrointestinal-tract-of-cynomolgus-monkeys
#20
Xin Li, Weiwei Yang, Xuran Li, Min Chen, Chengwei Liu, Shun Yu
Fibrillary α-synuclein (α-syn), which constitutes the major component of Lewy pathology characterized for Parkinson's disease (PD), is found also in the aged enteric nervous system (ENS) and central nervous system (CNS). However, what happens to oligomeric α-syn (o-α-syn) in the aged ENS and CNS remains poorly understood. Here, by using ELISA methods specific for o-α-syn and phosphorylated α-syn (p-α-syn), we measured the levels of o-α-syn and p-α-syn in the gastrointestinal (GI) tract and brain of aging cynomolgus monkeys...
October 26, 2017: Neuroscience Letters
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