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synuclein and aggregation

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https://www.readbyqxmd.com/read/28324300/%C3%AE-synuclein-and-parkinsonism-updates-and-future-perspectives
#1
REVIEW
Kaie Rosborough, Neha Patel, Lorraine V Kalia
Mutations in the SNCA gene, which encodes the α-synuclein protein, were the first discovered genetic causes of familial parkinsonism with Lewy pathology. To date, six different SNCA missense mutations as well as multiplications are known to cause parkinsonism. For this review, we performed a literature search to identify all published cases of SNCA-related parkinsonism to provide an updated summary of the clinical and neuropathological features of parkinsonism due to SNCA mutations. Familial parkinsonism associated with SNCA is rare, but α-synuclein aggregation is a core feature of sporadic parkinsonism, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy...
April 2017: Current Neurology and Neuroscience Reports
https://www.readbyqxmd.com/read/28323023/internalization-axonal-transport-and-release-of-fibrillar-forms-of-alpha-synuclein
#2
Gregor Bieri, Aaron D Gitler, Michel Brahic
Intra-neuronal protein aggregates made of fibrillar alpha-synuclein (α-syn) are the hallmark of Parkinson's disease (PD). With time, these aggregates spread through the brain following axonal projections. Understanding the mechanism of this spread is central to the study of the progressive nature of PD. Here we review data relevant to the uptake, transport and release of α-syn fibrils. We summarize several cell surface receptors that regulate the uptake of α-syn fibrils by neurons. The aggregates are then transported along axons, both in the anterograde and retrograde direction...
March 16, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28319736/structural-variants-in-snca-gene-and-the-implication-to-synucleinopathies
#3
REVIEW
Ornit Chiba-Falek
Synucleinopathies are a group of neurodegenerative diseases that share a common pathological lesion of intracellular protein inclusions largely composed of aggregates of alpha-synuclein protein. Accumulating evidence, including genome-wide association studies, has implicated the alpha-synuclein (SNCA) gene in the etiology of synucleinopathies and it has been suggested that SNCA expression levels are critical for the development of these diseases. This review focuses on genetic variants from the class of structural variants (SVs), including multiplication of large genomic segments and short (<50bp) genomic variants such as simple sequence repeats (SSRs), within the SNCA locus...
March 2, 2017: Current Opinion in Genetics & Development
https://www.readbyqxmd.com/read/28315001/ltb-syn-a-recombinant-immunogen-for-the-development-of-plant-made-vaccines-against-synucleinopathies
#4
Jaime I Arevalo-Villalobos, Dania O Govea-Alonso, Elizabeth Monreal-Escalante, Sergio Zarazúa, Sergio Rosales-Mendoza
A recombinant antigen targeting α-synuclein was produced in the plant cell rendering an immunogenic protein capable to induce humoral responses in mice upon oral administration. Synucleinopathies are neurodegenerative diseases characterized by the abnormal accumulation of α-synuclein (α-Syn, a 140 amino acid protein that normally plays various neurophysiologic roles) aggregates. Parkinson's disease (PD) is the synucleinopathy with the highest epidemiologic impact and although its etiology remains unknown, α-Syn aggregation during disease progression pointed out α-Syn as target in the development of immunotherapies...
March 17, 2017: Planta
https://www.readbyqxmd.com/read/28300150/s-nitrosylation-of-uchl1-induces-its-structural-instability-and-promotes-%C3%AE-synuclein-aggregation
#5
Roshan Kumar, Deepak K Jangir, Garima Verma, Shashi Shekhar, Pranita Hanpude, Sanjay Kumar, Raniki Kumari, Nirpendra Singh, Neel Sarovar Bhavesh, Nihar Ranjan Jana, Tushar Kanti Maiti
Ubiquitin C-terminal Hydrolase-1 (UCHL1) is a deubiquitinating enzyme, which plays a key role in Parkinson's disease (PD). It is one of the most important proteins, which constitute Lewy body in PD patient. However, how this well folded highly soluble protein presents in this proteinaceous aggregate is still unclear. We report here that UCHL1 undergoes S-nitrosylation in vitro and rotenone induced PD mouse model. The preferential nitrosylation in the Cys 90, Cys 152 and Cys 220 has been observed which alters the catalytic activity and structural stability...
March 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28297586/the-cleavage-effect-of-mesenchymal-stem-cell-and-its-derived-matrix-metalloproteinase-2-on-extracellular-%C3%AE-synuclein-aggregates-in-parkinsonian-models
#6
Se Hee Oh, Ha Na Kim, Hyun Jung Park, Jin Young Shin, Dong Yeol Kim, Phil Hyu Lee
Ample evidence has suggested that extracellular α-synuclein aggregates would play key roles in the pathogenesis and progression of Parkinsonian disorders (PDs). In the present study, we investigated whether mesenchymal stem cells (MSCs) and their derived soluble factors could exert neuroprotective effects via proteolysis of extracellular α-synuclein. When preformed α-synuclein aggregates were incubated with MSC-conditioned medium, α-synuclein aggregates were disassembled, and insoluble and oligomeric forms of α-synuclein were markedly decreased, thus leading to a significant increase in neuronal viability...
March 2017: Stem Cells Translational Medicine
https://www.readbyqxmd.com/read/28292187/distinct-mechanisms-determine-%C3%AE-synuclein-fibril-morphology-during-growth-and-maturation
#7
Arshdeep Sidhu, Ine Segers-Nolten, Vincent Raussens, Mireille M A E Claessens, Vinod Subramaniam
Amyloid polymorphs have become one of the focal points of molecular studies of neurodegenerative diseases like Parkinson's disease. Due to their distinct biochemical properties and prion-like characteristics, insights into the molecular origin and stability of amyloid polymorphs over time are crucial for understanding the potential role of amyloid polymorphism in these diseases. Here, we systematically study the fibrillization of recombinantly produced human α-synuclein (αSyn) over an extended period of time to unravel the origin and temporal evolution of polymorphism...
March 15, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28289488/copper-ii-and-the-pathological-h50q-%C3%AE-synuclein-mutant-environment-meets-genetics
#8
COMMENT
Anna Villar-Piqué, Giulia Rossetti, Salvador Ventura, Paolo Carloni, Claudio O Fernández, Tiago Fleming Outeiro
Copper is one of the metals described to bind the Parkinson disease-related protein α-synuclein (aSyn), and to promote its aggregation. Although histidine at position 50 in the aSyn sequence is one of the most studied copper-anchoring sites, its precise role in copper binding and aSyn aggregation is still unclear. Previous studies suggested that this residue does not significantly affect copper-mediated aSyn aggregation. However, our findings showed that the aggregation of the pathological H50Q aSyn mutant is enhanced by copper hints otherwise...
2017: Communicative & Integrative Biology
https://www.readbyqxmd.com/read/28289371/exosomes-origins-and-therapeutic-potential-for-neurodegenerative-disease
#9
REVIEW
Diana K Sarko, Cindy E McKinney
Exosomes, small lipid bilayer vesicles, are part of the transportable cell secretome that can be taken up by nearby recipient cells or can travel through the bloodstream to cells in distant organs. Selected cellular cytoplasm containing proteins, RNAs, and other macromolecules is packaged into secreted exosomes. This cargo has the potential to affect cellular function in either healthy or pathological ways. Exosomal content has been increasingly shown to assist in promoting pathways of neurodegeneration such as β-amyloid peptide (Aβ) accumulation forming amyloid plaques in the brains of patients with Alzheimer's disease, and pathological aggregates of proteins containing α-synuclein in Parkinson's disease transferred to the central nervous system via exosomes...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28288262/aggregation-of-%C3%AE-synuclein-in-the-gonadal-tissue-of-2-patients-with-parkinson-disease
#10
Alicia Garrido, Iban Aldecoa, Ellen Gelpi, Eduardo Tolosa
No abstract text is available yet for this article.
March 13, 2017: JAMA Neurology
https://www.readbyqxmd.com/read/28282814/the-synucleinopathies-twenty-years-on
#11
Michel Goedert, Ross Jakes, Maria Grazia Spillantini
In 2017, it is two hundred years since James Parkinson provided the first complete clinical description of the disease named after him, fifty years since the introduction of high-dose D,L-DOPA treatment and twenty years since α-synuclein aggregation came to the fore. In 1998, multiple system atrophy joined Parkinson's disease and dementia with Lewy bodies as the third major synucleinopathy. Here we review our work, which led to the identification of α-synuclein in Lewy bodies, Lewy neurites and Papp-Lantos bodies, as well as what has happened since...
2017: Journal of Parkinson's Disease
https://www.readbyqxmd.com/read/28276260/holothuria-scabra-extracts-exhibit-anti-parkinson-potential-in-c-elegans-a-model-for-anti-parkinson-testing
#12
Pawanrat Chalorak, Prapaporn Jattujan, Saksit Nobsathian, Tanate Poomtong, Prasert Sobhon, Krai Meemon
OBJECTIVES: Parkinson's disease (PD) is associated with aggregation of α-synuclein and selective death of dopaminergic (DA) neurons in the substantia nigra, thereby leading to cognitive and motor impairments. Nowadays, the drugs commonly used for PD treatment, such as levodopa, provide only symptomatic relief. Therefore, seeking new drugs against PD, especially from plants and marine organisms, is one of the major research areas to be explored. This study aimed to investigate the anti-Parkinson activity of the extracts from the sea cucumber, Holothuria scabra, by using Caenorhabditis elegans as a model...
March 9, 2017: Nutritional Neuroscience
https://www.readbyqxmd.com/read/28272426/post-translational-modifications-in-prp-expand-the-conformational-diversity-of-prions-in-vivo
#13
Patricia Aguilar-Calvo, Xiangzhu Xiao, Cyrus Bett, Hasier Eraña, Katrin Soldau, Joaquin Castilla, K Peter R Nilsson, Witold K Surewicz, Christina J Sigurdson
Misfolded prion protein aggregates (PrP(Sc)) show remarkable structural diversity and are associated with highly variable disease phenotypes. Similarly, other proteins, including amyloid-β, tau, α-synuclein, and serum amyloid A, misfold into distinct conformers linked to different clinical diseases through poorly understood mechanisms. Here we use mice expressing glycophosphatidylinositol (GPI)-anchorless prion protein, PrP(C), together with hydrogen-deuterium exchange coupled with mass spectrometry (HXMS) and a battery of biochemical and biophysical tools to investigate how post-translational modifications impact the aggregated prion protein properties and disease phenotype...
March 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28269775/reduction-of-rpt6-s8-a-proteasome-component-and-proteasome-activity-in-the-cortex-is-associated-with-cognitive-impairment-in-lewy-body-dementia
#14
Amani Alghamdi, Julie Vallortigara, David R Howlett, Martin Broadstock, Tibor Hortobágyi, Clive Ballard, Alan J Thomas, John T O'Brien, Dag Aarsland, Johannes Attems, Paul T Francis, David R Whitfield
Lewy body dementia is the second most common neurodegenerative dementia and is pathologically characterized by α-synuclein positive cytoplasmic inclusions, with varying amounts of amyloid-β (Aβ) and hyperphosphorylated tau (tau) aggregates in addition to synaptic loss. A dysfunctional ubiquitin proteasome system (UPS), the major proteolytic pathway responsible for the clearance of short lived proteins, may be a mediating factor of disease progression and of the development of α-synuclein aggregates. In the present study, protein expression of a key component of the UPS, the RPT6 subunit of the 19S regulatory complex was determined...
March 1, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28265088/correction-for-perni-et-al-a-natural-product-inhibits-the-initiation-of-%C3%AE-synuclein-aggregation-and-suppresses-its-toxicity
#15
(no author information available yet)
No abstract text is available yet for this article.
March 6, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28259991/the-involvement-of-eag1-potassium-channels-and-mir-34a-in-rotenone-induced-death-of-dopaminergic-sh-sy5y-cells
#16
Camila Hillesheim Horst, Ricardo Titze-de-Almeida, Simoneide Souza Titze-de-Almeida
The loss of dopaminergic neurons and the resultant motor impairment are hallmarks of Parkinson's disease. The SH‑SY5Y cell line is a model of dopaminergic neurons, and allows for the study of dopaminergic neuronal injury. Previous studies have revealed changes in Ether à go‑go 1 (Eag1) potassium channel expression during p53-induced SH‑SY5Y apoptosis, and the regulatory involvement of microRNA‑34a (miR‑34a) was demonstrated. In the present study, the involvement of Eag1 and miR‑34a in rotenone‑induced SH‑SY5Y cell injury was investigated...
February 10, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28257421/the-mechanism-of-sirtuin-2-mediated-exacerbation-of-alpha-synuclein-toxicity-in-models-of-parkinson-disease
#17
Rita Machado de Oliveira, Hugo Vicente Miranda, Laetitia Francelle, Raquel Pinho, Éva M Szegö, Renato Martinho, Francesca Munari, Diana F Lázaro, Sébastien Moniot, Patrícia Guerreiro, Luis Fonseca, Zrinka Marijanovic, Pedro Antas, Ellen Gerhardt, Francisco Javier Enguita, Bruno Fauvet, Deborah Penque, Teresa Faria Pais, Qiang Tong, Stefan Becker, Sebastian Kügler, Hilal Ahmed Lashuel, Clemens Steegborn, Markus Zweckstetter, Tiago Fleming Outeiro
Sirtuin genes have been associated with aging and are known to affect multiple cellular pathways. Sirtuin 2 was previously shown to modulate proteotoxicity associated with age-associated neurodegenerative disorders such as Alzheimer and Parkinson disease (PD). However, the precise molecular mechanisms involved remain unclear. Here, we provide mechanistic insight into the interplay between sirtuin 2 and α-synuclein, the major component of the pathognomonic protein inclusions in PD and other synucleinopathies...
March 2017: PLoS Biology
https://www.readbyqxmd.com/read/28257086/high-throughput-screening-methodology-to-identify-alpha-synuclein-aggregation-inhibitors
#18
Jordi Pujols, Samuel Peña-Díaz, María Conde-Giménez, Francisca Pinheiro, Susanna Navarro, Javier Sancho, Salvador Ventura
An increasing number of neurodegenerative diseases are being found to be associated with the abnormal accumulation of aggregated proteins in the brain. In Parkinson's disease, this process involves the aggregation of alpha-synuclein (α-syn) into intraneuronal inclusions. Thus, compounds that inhibit α-syn aggregation represent a promising therapeutic strategy as disease-modifying agents for neurodegeneration. The formation of α-syn amyloid aggregates can be reproduced in vitro by incubation of the recombinant protein...
March 2, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28249224/a-moderate-metal-binding-hydrazone-meets-the-criteria-for-a-bioinorganic-approach-towards-parkinson-s-disease-therapeutic-potential-blood-brain-barrier-crossing-evaluation-and-preliminary-toxicological-studies
#19
Daphne Schneider Cukierman, Ana Beatriz Pinheiro, Sergio L P Castiñeiras-Filho, Anastácia Sá P da Silva, Marco C Miotto, Anna De Falco, Thales de P Ribeiro, Silvia Maisonette, Alessandra L M C da Cunha, Rachel A Hauser-Davis, J Landeira-Fernandez, Ricardo Q Aucélio, Tiago F Outeiro, Marcos D Pereira, Claudio O Fernández, Nicolás A Rey
Alzheimer's and Parkinson's diseases share similar amyloidogenic mechanisms, in which metal ions might play an important role. In this last neuropathy, misfolding and aggregation of α-synuclein (α-Syn) are crucial pathological events. A moderate metal-binding compound, namely, 8-hydroxyquinoline-2-carboxaldehyde isonicotinoyl hydrazone (INHHQ), which was previously reported as a potential 'Metal-Protein Attenuating Compound' for Alzheimer's treatment, is well-tolerated by healthy Wistar rats and does not alter their major organ weights, as well as the tissues' reduced glutathione and biometal levels, at a concentration of 200mgkg(-1)...
February 22, 2017: Journal of Inorganic Biochemistry
https://www.readbyqxmd.com/read/28241427/potential-modes-of-intercellular-%C3%AE-synuclein-transmission
#20
REVIEW
Dario Valdinocci, Rowan A W Radford, Sue Maye Siow, Roger S Chung, Dean L Pountney
Intracellular aggregates of the α-synuclein protein result in cell loss and dysfunction in Parkinson's disease and atypical Parkinsonism, such as multiple system atrophy and dementia with Lewy bodies. Each of these neurodegenerative conditions, known collectively as α-synucleinopathies, may be characterized by a different suite of molecular triggers that initiate pathogenesis. The mechanisms whereby α-synuclein aggregates mediate cytotoxicity also remain to be fully elucidated. However, recent studies have implicated the cell-to-cell spread of α-synuclein as the major mode of disease propagation between brain regions during disease progression...
February 22, 2017: International Journal of Molecular Sciences
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