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synuclein and aggregation

A D Surowka, M Töpperwien, M Bernhardt, J D Nicolas, M Osterhoff, T Salditt, D Adamek, M Szczerbowska-Boruchowska
Human dopaminergic system in general, and substantia nigra (SN) neurons, in particular, are implicated in the pathologies underlying the human brain aging. The interplay between aberrations in the structural organization and elemental composition of SN neuron bodies has recently gained in importance as selected metals: Fe, Cu, Zn, Ca were found to trigger oxidative-stress-mediated aberration in their molecular assembly due to concomitant protein (alpha-synuclein, tau-protein) aggregation, gliosis and finally oxidative stress...
December 1, 2016: Talanta
Graham Fairfoul, Lynne I McGuire, Suvankar Pal, James W Ironside, Juliane Neumann, Sharon Christie, Catherine Joachim, Margaret Esiri, Samuel G Evetts, Michal Rolinski, Fahd Baig, Claudio Ruffmann, Richard Wade-Martins, Michele T M Hu, Laura Parkkinen, Alison J E Green
We have developed a novel real-time quaking-induced conversion RT-QuIC-based assay to detect alpha-synuclein aggregation in brain and cerebrospinal fluid from dementia with Lewy bodies and Parkinson's disease patients. This assay can detect alpha-synuclein aggregation in Dementia with Lewy bodies and Parkinson's disease cerebrospinal fluid with sensitivities of 92% and 95%, respectively, and with an overall specificity of 100% when compared to Alzheimer and control cerebrospinal fluid. Patients with neuropathologically confirmed tauopathies (progressive supranuclear palsy; corticobasal degeneration) gave negative results...
October 2016: Annals of Clinical and Translational Neurology
Hye-Jin Park, Kang-Woo Lee, Eun S Park, Stephanie Oh, Run Yan, Jie Zhang, Thomas G Beach, Charles H Adler, Michael Voronkov, Steven P Braithwaite, Jeffry B Stock, M Maral Mouradian
OBJECTIVE: Protein phosphatase 2A (PP2A) is a heterotrimeric holoenzyme composed of a catalytic C subunit, a structural A subunit, and one of several regulatory B subunits that confer substrate specificity. The assembly and activity of PP2A are regulated by reversible methylation of the C subunit. α-Synuclein, which aggregates in Parkinson disease (PD) and dementia with Lewy bodies (DLB), is phosphorylated at Ser129, and PP2A containing a B55α subunit is a major phospho-Ser129 phosphatase...
October 2016: Annals of Clinical and Translational Neurology
Alexandre N Rcom-H'cheo-Gauthier, Amelia Davis, Adrian C B Meedeniya, Dean L Pountney
α-Synuclein (α-syn) aggregates (Lewy bodies) in dementia with Lewy Bodies (DLB) may be associated with disturbed calcium homeostasis and oxidative stress. We investigated the interplay between α-syn aggregation, expression of the calbindin-D28k (CB) neuronal calcium-buffering protein and oxidative stress, combining immunofluorescence double labelling and Western analysis, and examining DLB and normal human cases and a unilateral oxidative stress lesion model of α-syn disease (rotenone mouse). DLB cases showed a greater proportion of CB+ cells in affected brain regions compared to normal cases with Lewy bodies largely present in CB- neurons and virtually undetected in CB+ neurons...
October 13, 2016: Molecular and Cellular Neurosciences
Kai-Chih Hung, Hui-Ju Huang, Yi-Ting Wang, Anya Maan-Yuh Lin
ETHNOPHARMACOLOGICAL RELEVANCE: Neuroinflammation, oxidative stress, and protein aggregation form a vicious cycle in the pathophysiology of Parkinson's disease (PD); activated microglia is the main location of neuroinflammation. A Chinese medicine book, "Shanghan Lun", known as the "Treatises on Cold damage Diseases" has suggested that Scutellaria baicalensis Georgi is effective in treating CNS diseases. The anti-inflammatory mechanisms of baicalein, a phenolic flavonoid in the dried root of Scutellaria baicalensis Georgi, remain to be explored...
October 11, 2016: Journal of Ethnopharmacology
Dhiman Ghosh, Surabhi Mehra, Shruti Sahay, Pradeep K Singh, Samir K Maji
Parkinson's disease (PD) is a neurological disorder marked by the presence of cytoplasmic inclusions, Lewy bodies (LBs) and Lewy neurites (LNs) as well as the degeneration of dopamine producing neurons in the substantia nigra region of the brain. The LBs and LNs in PD are mainly composed of aggregated form of a presynaptic protein, α-synuclein (α-Syn). However, the mechanisms of α-Syn aggregation and actual aggregated species responsible for the degeneration of dopaminergic neurons have not yet been resolved...
October 10, 2016: International Journal of Biological Macromolecules
Neal K Bennett, Rebecca Chmielowski, Dalia S Abdelhamid, Jonathan J Faig, Nicola Francis, Jean Baum, Zhiping P Pang, Kathryn E Uhrich, Prabhas V Moghe
Neuroinflammation, a common neuropathologic feature of neurodegenerative disorders including Parkinson disease (PD), is frequently exacerbated by microglial activation. The extracellular protein α-synuclein (ASYN), whose aggregation is characteristic of PD, remains a key therapeutic target, but the control of synuclein trafficking and aggregation within microglia has been challenging. First, we established that microglial internalization of monomeric ASYN was mediated by scavenger receptors (SR), CD36 and SRA1, and was rapidly accompanied by the formation of ASYN oligomers...
December 2016: Biomaterials
Marthe H R Ludtmann, Plamena R Angelova, Natalia N Ninkina, Sonia Gandhi, Vladimir L Buchman, Andrey Y Abramov
: Misfolded α-synuclein is a key factor in the pathogenesis of Parkinson's disease (PD). However, knowledge about a physiological role for the native, unfolded α-synuclein is limited. Using brains of mice lacking α-, β-, and γ-synuclein, we report that extracellular monomeric α-synuclein enters neurons and localizes to mitochondria, interacts with ATP synthase subunit α, and modulates ATP synthase function. Using a combination of biochemical, live-cell imaging and mitochondrial respiration analysis, we found that brain mitochondria of α-, β-, and γ-synuclein knock-out mice are uncoupled, as characterized by increased mitochondrial respiration and reduced mitochondrial membrane potential...
October 12, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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...
October 11, 2016: Stem Cells Translational Medicine
Keqiang Chen, Ruoxi Yuan, Shuo Geng, Yao Zhang, Taojing Ran, Elizabeth Kowalski, Jingze Liu, Liwu Li
The excessive accumulation of specific cellular proteins or autophagic vacuoles (AVs) within neurons is a pathologic hallmark of neurodegenerative diseases. Constitutive autophagy in neurons prevents abnormal intracellular protein aggregation and is critical for maintaining cell survival. Since our previous study showed that Toll-interacting protein (Tollip)-deficient macrophages had constitutive disruption of endosome-lysosome fusion, we hypothesize that Tollip deficiency may also promote neuron death via blockage of autophagy completion...
October 5, 2016: Brain, Behavior, and Immunity
Andrea Lee, Rebecca M Gilbert
Parkinson disease (PD) is a common progressive neurodegenerative condition, causing both motor and non motor symptoms. Motor symptoms include stiffness, slowness, rest tremor and poor postural reflexes, whereas nonmotor symptoms include abnormalities of mood, cognition, sleep and autonomic function. Affected patients show cell loss in the substantia nigra pars compacta, and accumulation of aggregated alpha-synuclein into intracellular structures called Lewy bodies, within specific brain regions. The main known non modifiable risk factor is age...
November 2016: Neurologic Clinics
Lin Kooi Ong, Zidan Zhao, Murielle Kluge, Clifford TeBay, Katarzyna Zalewska, Phillip W Dickson, Sarah J Johnson, Michael Nilsson, Frederick R Walker
Exposure to psychological stress is known to seriously disrupt the operation of the substantia nigra (SN) and may in fact initiate the loss of dopaminergic neurons within the SN. In this study, we aimed to investigate how chronic stress modified the SN in adult male mice. Using a paradigm of repeated restraint stress (an average of 20 h per week for 6 weeks), we examined changes within the SN using a combination of western blotting and immunohistochemistry approaches. We demonstrated that chronic stress was associated with a clear loss of dopaminergic neurons within the SN...
October 4, 2016: Brain, Behavior, and Immunity
Saida Abounit, Jessica W Wu, Guiliana Soraya Victoria, Chiara Zurzolo
The mechanisms of intercellular spreading of amyloidogenic proteins involved in neurodegenerative diseases have yet to be fully elucidated. While secretion has been implicated in the transfer of many proteins, including prions and α-synuclein, tunneling nanotubes (TNTs) have also been demonstrated for prions and mutant Huntingtin. Here, we provide further evidence that Tau aggregates, which have been demonstrated to predominantly be transferred via secretion, can also be found in TNTs. Additionally cells that have taken up Tau have increased TNT formation...
October 7, 2016: Prion
Mrigendra Bir Karmacharya, Binika Hada, So Ra Park, Byung Hyune Choi
Many studies have shown that mitochondrial dysfunction and the subsequent oxidative stress caused by excessive reactive oxygen species (ROS) generation play a central role in the pathogenesis of Parkinson's disease (PD). We have previously shown that low-intensity ultrasound (LIUS) could reduce ROS generation by L-buthionine-(S,R)-sulfoximine (BSO) in retinal pigment epithelial cells. In this study, we studied the effects of LIUS stimulation on the ROS-dependent α-synuclein aggregation in 1-methyl-4-phenylpyridinium ion (MPP(+))-treated PC12 cells...
October 6, 2016: Molecular Neurobiology
Limin Hao, Oshrit Ben-David, Suzann M Babb, Anthony H Futerman, Bruce M Cohen, Edgar A Buttner
Defining the mechanisms of action of the anti-psychotic drug (APD), clozapine is of great importance, as clozapine is more effective and has therapeutic benefits in a broader range of psychiatric disorders than other APDs. Its range of actions have not been fully characterized. Exposure to APDs early in development causes dose-dependent developmental delay and lethality in C. elegans. A previous genome-wide RNAi screen for suppressors of clozapine-induced developmental delay and lethality revealed 40 candidate genes, including sms-1, which encodes a sphingomyelin synthase...
October 6, 2016: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Shu G Chen, Vilius Stribinskis, Madhavi J Rane, Donald R Demuth, Evelyne Gozal, Andrew M Roberts, Rekha Jagadapillai, Ruolan Liu, Kyonghwan Choe, Bhooma Shivakumar, Francheska Son, Shunying Jin, Richard Kerber, Anthony Adame, Eliezer Masliah, Robert P Friedland
Misfolded alpha-synuclein (AS) and other neurodegenerative disorder proteins display prion-like transmission of protein aggregation. Factors responsible for the initiation of AS aggregation are unknown. To evaluate the role of amyloid proteins made by the microbiota we exposed aged rats and transgenic C. elegans to E. coli producing the extracellular bacterial amyloid protein curli. Rats exposed to curli-producing bacteria displayed increased neuronal AS deposition in both gut and brain and enhanced microgliosis and astrogliosis compared to rats exposed to either mutant bacteria unable to synthesize curli, or to vehicle alone...
October 6, 2016: Scientific Reports
Anna Villar-Piqué, Tomás Lopes da Fonseca, Ricardo Sant'Anna, Éva Mónika Szegö, Luis Fonseca-Ornelas, Raquel Pinho, Anita Carija, Ellen Gerhardt, Caterina Masaracchia, Enrique Abad Gonzalez, Giulia Rossetti, Paolo Carloni, Claudio O Fernández, Debora Foguel, Ira Milosevic, Markus Zweckstetter, Salvador Ventura, Tiago Fleming Outeiro
Synucleinopathies are a group of progressive disorders characterized by the abnormal aggregation and accumulation of α-synuclein (aSyn), an abundant neuronal protein that can adopt different conformations and biological properties. Recently, aSyn pathology was shown to spread between neurons in a prion-like manner. Proteins like aSyn that exhibit self-propagating capacity appear to be able to adopt different stable conformational states, known as protein strains, which can be modulated both by environmental and by protein-intrinsic factors...
October 5, 2016: Proceedings of the National Academy of Sciences of the United States of America
Michael F Almeida, Carolliny M Silva, Aline M D'Unhao, Merari F R Ferrari
Cell physiology is impaired before protein aggregation and this may be more relevant than inclusions themselves for neurodegeneration. The present study aimed to characterize an animal model to enable the analysis of the cell biology before and after protein aggregation. Ten-month-old Lewis rats were exposed either to 1 or 2 mg/kg/day of rotenone, delivered subcutaneously through mini-pumps, for one month. Hyperphosphorylated TAU, alpha-synuclein, amyloid-beta peptide and protein carbonylation (indicative of oxidative stress) were evaluated in the hippocampus, substantia nigra and locus coeruleus through immunohistochemistry or western blot...
September 2016: Arquivos de Neuro-psiquiatria
Yoshihide Takeshita, Nobuto Shibata, Koji Kasanuki, Tomoyuki Nagata, Shunichiro Shinagawa, Nobuyuki Kobayashi, Tohru Ohnuma, Ayako Suzuki, Eri Kawai, Toshiki Takayama, Kenya Nishioka, Yumiko Motoi, Nobutaka Hattori, Kazuhiko Nakayama, Hisashi Yamada, Heii Arai
BACKGROUND/AIMS: Interaction of receptor for advanced glycation end products (RAGE) with amyloid-β increases amplification of oxidative stress and plays pathological roles in Alzheimer's disease (AD). Oxidative stress leads to α-synuclein aggregation and is also a major contributing factor in the pathogenesis of Lewy body dementias (LBDs). Therefore, we aimed to investigate whether RAGE gene polymorphisms were associated with AD and LBDs. METHODS: Four single nucleotide polymorphisms (SNPs)-rs1800624, rs1800625, rs184003, and rs2070600-of the gene were analyzed using a case-control study design comprising 288 AD patients, 76 LBDs patients, and 105 age-matched controls...
October 4, 2016: International Journal of Geriatric Psychiatry
Srivastav Ranganathan, Samir K Maji, Ranjith Padinhateeri
Self-assembly of proteins into ordered, fibrillar structures is a commonly observed theme in biology. It has been observed that diverse set of proteins (e.g alpha-synuclein, insulin, TATA-box binding protein, Sup35, p53), independent of their sequence, native structure, or function could self-assemble into highly ordered structures known as amyloids. What are the crucial features underlying amyloidogenesis that make it so generic? Using coarse-grained simulations of peptide self-assembly, we argue that variation in two physical parameters- bending-stiffness of the polypeptide and strength of inter-molecular interactions- can give rise to many of the structural features typically associated with amyloid self-assembly...
October 3, 2016: Journal of the American Chemical Society
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