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alpha synuclein and aggregation

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https://www.readbyqxmd.com/read/28623611/deferiprone-rescues-behavioral-deficits-induced-by-mild-iron-exposure-in-a-mouse-model-of-alpha-synuclein-aggregation
#1
Eleonora Carboni, Lars Tatenhorst, Lars Tönges, Elisabeth Barski, Vivian Dambeck, Mathias Bähr, Paul Lingor
Parkinson's disease (PD) is the most common neurodegenerative movement disorder, and its causes remain unknown. A major hallmark of the disease is the increasing presence of aggregated alpha-synuclein (aSyn). Furthermore, there is a solid consensus on iron (Fe) accumulation in several regions of PD brains during disease progression. In our study, we focused on the interaction of Fe and aggregating aSyn in vivo in a transgenic mouse model overexpressing human aSyn bearing the A53T mutation (prnp.aSyn.A53T). We utilized a neonatal iron-feeding model to exacerbate the motor phenotype of the transgenic mouse model...
June 16, 2017: Neuromolecular Medicine
https://www.readbyqxmd.com/read/28611062/selective-imaging-of-internalized-proteopathic-%C3%AE-synuclein-seeds-in-primary-neurons-reveals-mechanistic-insight-into-transmission-of-synucleinopathies
#2
Richard J Karpowicz, Conor M Haney, Tiberiu S Mihaila, Raizel M Sandler, E James Petersson, Virginia M-Y Lee
Direct cell-to-cell transmission of proteopathic alpha-synuclein (α-syn) aggregates is thought to underlie the progression of neurodegenerative synucleinopathies. However, the specific intracellular processes governing this transmission remain unclear because currently-available model systems are limited. For example, in cell culture models of α-syn-seeded aggregation, it is difficult to discern intracellular from extracellular exogenously applied α-syn seed species. Herein, we employed fluorescently labeled α-syn preformed fibrils (pffs) in conjunction with the membrane-impermeable fluorescence quencher trypan blue to selectively image internalized α-syn seeds in cultured primary neurons and to quantitatively characterize the concentration dependence, time course, and inhibition of pff uptake...
June 13, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28598856/glucocerebrosidase-mutations-in-parkinson-disease
#3
Grace O'Regan, Ruth-Mary deSouza, Roberta Balestrino, A H Schapira
Following the discovery of a higher than expected incidence of Parkinson Disease (PD) in Gaucher disease, a lysosomal storage disorder, mutations in the glucocerebrocidase (GBA) gene, which encodes a lysosomal enzyme involved in sphingolipid degradation were explored in the context of idiopathic PD. GBA mutations are now known to be the single largest risk factor for development of idiopathic PD. Clinically, on imaging and pharmacologically, GBA PD is almost identical to idiopathic PD. In patients with a known GBA mutation, it is possible to monitor for prodromal signs of PD...
June 7, 2017: Journal of Parkinson's Disease
https://www.readbyqxmd.com/read/28579939/the-role-of-co-chaperones-in-synaptic-proteostasis-and-neurodegenerative-disease
#4
REVIEW
Erica L Gorenberg, Sreeganga S Chandra
Synapses must be preserved throughout an organism's lifespan to allow for normal brain function and behavior. Synapse maintenance is challenging given the long distances between the termini and the cell body, reliance on axonal transport for delivery of newly synthesized presynaptic proteins, and high rates of synaptic vesicle exo- and endocytosis. Hence, synapses rely on efficient proteostasis mechanisms to preserve their structure and function. To this end, the synaptic compartment has specific chaperones to support its functions...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28571531/c-abl-inhibition-a-novel-therapeutic-target-for-parkinson-s-disease
#5
Abdelrahman Ibrahim Abushouk, Ahmed Negida, Rasha Abdelsalam Elshenawy, Hossam Zein, Ali M Hammad, Ahmed Menshawy, Wael M Y Mohamed
Parkinson's disease (PD) is the most prevalent movement disorder in the world. The major pathological hallmarks of PD are death of dopaminergic neurons and the formation of Lewy bodies. To the moment, there is no cure for PD; current treatments are symptomatic. Investigators are searching for neuroprotective agents and disease modifying strategies to slow the progress of PD. However, due to ignorance of the main pathological sequence of PD, many drug targets failed recently to provide neuroprotective effects in human trials...
June 1, 2017: CNS & Neurological Disorders Drug Targets
https://www.readbyqxmd.com/read/28540131/parkinson-s-disease-microglial-macrophage-induced-immunoexcitotoxicity-as-a-central-mechanism-of-neurodegeneration
#6
REVIEW
Russell L Blaylock
Parkinson's disease is one of the several neurodegenerative disorders that affects aging individuals, with approximately 1% of those over the age of 60 years developing the disorder in their lifetime. The disease has the characteristics of a progressive disorder in most people, with a common pattern of pathological change occurring in the nervous system that extends beyond the classical striatal degeneration of dopaminergic neurons. Earlier studies concluded that the disease was a disorder of alpha-synuclein, with the formation of aggregates of abnormal alpha-synuclein being characteristic...
2017: Surgical Neurology International
https://www.readbyqxmd.com/read/28534083/synthetic-alpha-synuclein-fibrils-cause-mitochondrial-impairment-and-selective-dopamine-neurodegeneration-in-part-via-inos-mediated-nitric-oxide-production
#7
Victor Tapias, Xiaoping Hu, Kelvin C Luk, Laurie H Sanders, Virginia M Lee, J Timothy Greenamyre
Intracellular accumulation of α-synuclein (α-syn) are hallmarks of synucleinopathies, including Parkinson's disease (PD). Exogenous addition of preformed α-syn fibrils (PFFs) into primary hippocampal neurons induced α-syn aggregation and accumulation. Likewise, intrastriatal inoculation of PFFs into mice and non-human primates generates Lewy bodies and Lewy neurites associated with PD-like neurodegeneration. Herein, we investigate the putative effects of synthetic human PFFs on cultured rat ventral midbrain dopamine (DA) neurons...
May 22, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28450268/extensive-uptake-of-%C3%AE-synuclein-oligomers-in-astrocytes-results-in-sustained-intracellular-deposits-and-mitochondrial-damage
#8
Veronica Lindström, Gabriel Gustafsson, Laurie H Sanders, Evan H Howlett, Jessica Sigvardson, Alex Kasrayan, Martin Ingelsson, Joakim Bergström, Anna Erlandsson
The presence of Lewy bodies, mainly consisting of aggregated α-synuclein, is a pathological hallmark of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). The α-synuclein inclusions are predominantly found in neurons, but also appear frequently in astrocytes. However, the pathological significance of α-synuclein inclusions in astrocytes and the capacity of glial cells to clear toxic α-synuclein species remain unknown. In the present study we investigated uptake, degradation and toxic effects of oligomeric α-synuclein in a co-culture system of primary neurons, astrocytes and oligodendrocytes...
April 24, 2017: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/28439961/involvement-of-the-cerebellum-in-parkinson-disease-and-dementia-with-lewy-bodies
#9
Kay Seidel, Mohamed Bouzrou, Nina Heidemann, Rejko Krüger, Ludger Schöls, Wilfred F A den Dunnen, Horst-Werner Korf, Udo Rüb
Brains from patients with Parkinson disease or dementia with Lewy bodies show aggregation of alpha-synuclein in precerebellar brainstem structures. Furthermore, patients exhibit resting tremor, unstable gait, and impaired balance, which may be associated with cerebellar dysfunction. Therefore, we screened the cerebella of 12 patients with alpha-synucleinopathies for neuropathological changes. Cerebellar nuclei and neighboring white matter displayed numerous aggregates, whereas lobules were mildly affected. Cerebellar aggregation pathology may suggest a prionlike spread originating from affected precerebellar structures, and the high homogeneity between patients with dementia with Lewy bodies and Parkinson disease shows that both diseases likely belong to the same neuropathological spectrum...
June 2017: Annals of Neurology
https://www.readbyqxmd.com/read/28425704/an-ortho-iminoquinone-compound-reacts-with-lysine-inhibiting-aggregation-while-remodeling-mature-amyloid-fibrils
#10
Luiza Fernandes, Nathalia Moraes, Fernanda S Sagrillo, Augusto V Magalhães, Marcela C de Moraes, Luciana Romão, Jeffery W Kelly, Debora Foguel, Neil P Grimster, Fernando L Palhano
Protein aggregation is a hallmark of several neurodegenerative diseases, including Alzheimer's and Parkinson's diseases. It has been shown that lysine residues play a key role in the formation of these aggregates. Thus, the ability to disrupt aggregate formation by covalently modifying lysine residues could lead to the discovery of therapeutically relevant antiamyloidogenesis compounds. Herein, we demonstrate that an ortho-iminoquinone (IQ) can be utilized to inhibit amyloid aggregation. Using alpha-synuclein and Aβ1-40 as model amyloidogenic proteins, we observed that IQ was able to react with lysine residues and reduce amyloid aggregation...
May 4, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28424577/investigation-of-endocytic-pathways-for-the-internalization-of-exosome-associated-oligomeric-alpha-synuclein
#11
Marion Delenclos, Teodora Trendafilova, Divya Mahesh, Ann M Baine, Simon Moussaud, Irene K Yan, Tushar Patel, Pamela J McLean
Misfolding and aggregation of alpha-synuclein (αsyn) resulting in cytotoxicity is a hallmark of Parkinson's disease (PD) and related synucleinopathies. The recent body of evidence indicates that αsyn can be released from neuronal cells by nonconventional exocytosis involving extracellular vesicles (EVs) such as exosomes. The transfer of αsyn between cells has been proposed to be an important mechanism of disease propagation in PD. To date, exosome trafficking mechanisms, including release and cell-cell transmission, have not been fully described...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28420950/metallothionein-copper-and-alpha-synuclein-in-alpha-synucleinopathies
#12
REVIEW
Yuho Okita, Alexandre N Rcom-H'cheo-Gauthier, Michael Goulding, Roger S Chung, Peter Faller, Dean L Pountney
Metallothioneins (MTs) are proteins that function by metal exchange to regulate the bioavailability of metals, such as zinc and copper. Copper functions in the brain to regulate mitochondria, neurotransmitter production, and cell signaling. Inappropriate copper binding can result in loss of protein function and Cu(I)/(II) redox cycling can generate reactive oxygen species. Copper accumulates in the brain with aging and has been shown to bind alpha-synuclein and initiate its aggregation, the primary aetiological factor in Parkinson's disease (PD), and other alpha-synucleinopathies...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28419566/perirhinal-accumulation-of-neuronal-alpha-synuclein-in-a-multiple-system-atrophy-patient-with-dementia
#13
Mari Saito, Makoto Hara, Momoko Ebashi, Akihiko Morita, Kyoko Okada, Taku Homma, Masahiko Sugitani, Kentaro Endo, Toshiki Uchihara, Satoshi Kamei
We report the case of a 79-year-old Japanese woman who developed cerebellar ataxia followed by rigidity, dysautonomia and cognitive disorders, and was thus clinically diagnosed as having possible MSA with dementia. Neuropathological findings demonstrated not only olivopontocerebellar and striatonigral degeneration with frequent glial cytoplasmic inclusions (GCIs), but also degenerative changes in the parahippocampal region, accentuated in the anterior portion of perirhinal cortex, where neuronal cytoplasmic inclusions (NCIs) and NFTs were numerous while GCIs were limited...
April 16, 2017: Neuropathology: Official Journal of the Japanese Society of Neuropathology
https://www.readbyqxmd.com/read/28400134/alpha-synuclein-pathology-mitochondrial-dysfunction-and-neuroinflammation-in-parkinson-s-disease
#14
REVIEW
Emily M Rocha, Briana De Miranda, Laurie H Sanders
Parkinson's disease (PD) is a complex, chronic and progressive neurodegenerative disease. While the etiology of PD is likely multifactorial, the protein α-synuclein is a central component to the pathogenesis of the disease. However, the mechanism by which α-synuclein causes toxicity and contributes to neuronal death remains unclear. Mitochondrial dysfunction is also widely considered to play a major role in the underlying mechanisms contributing to neurodegeneration in PD. This review discusses evidence for the neuropathological role for α-synuclein in the dysfunction of dopamine neurons in PD...
April 8, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28378233/multiple-system-atrophy-state-of-the-art
#15
REVIEW
Brice Laurens, Sylvain Vergnet, Miguel Cuina Lopez, Alexandra Foubert-Samier, François Tison, Pierre-Olivier Fernagut, Wassilios G Meissner
Multiple system atrophy (MSA) is a rare and fatal neurodegenerative disorder that is characterized by a variable combination of parkinsonism, cerebellar impairment, and autonomic dysfunction. Some symptomatic treatments are available while neuroprotection or disease-modification remain unmet treatment needs. The pathologic hallmark is the accumulation of aggregated alpha-synuclein (α-syn) in oligodendrocytes forming glial cytoplasmic inclusions, which qualifies MSA as synucleinopathy together with Parkinson's disease and dementia with Lewy bodies...
May 2017: Current Neurology and Neuroscience Reports
https://www.readbyqxmd.com/read/28351932/seeding-and-transgenic-overexpression-of-alpha-synuclein-triggers-dendritic-spine-pathology-in-the-neocortex
#16
Sonja Blumenstock, Eva F Rodrigues, Finn Peters, Lidia Blazquez-Llorca, Felix Schmidt, Armin Giese, Jochen Herms
Although misfolded and aggregated α-synuclein (α-syn) is recognized in the disease progression of synucleinopathies, its role in the impairment of cortical circuitries and synaptic plasticity remains incompletely understood. We investigated how α-synuclein accumulation affects synaptic plasticity in the mouse somatosensory cortex using two distinct approaches. Long-term in vivo imaging of apical dendrites was performed in mice overexpressing wild-type human α-synuclein. Additionally, intracranial injection of preformed α-synuclein fibrils was performed to induce cortical α-syn pathology...
May 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28323023/internalization-axonal-transport-and-release-of-fibrillar-forms-of-alpha-synuclein
#17
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
#18
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...
June 2017: Current Opinion in Genetics & Development
https://www.readbyqxmd.com/read/28259991/the-involvement-of-eag1-potassium-channels-and-mir-34a-in-rotenone-induced-death-of-dopaminergic-sh-sy5y-cells
#19
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...
April 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
#20
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-Ornelas, 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
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