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alpha 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
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
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
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
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
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
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
Yu Funahashi, Yuta Yoshino, Kiyohiro Yamazaki, Yoko Mori, Takaaki Mori, Yuki Ozaki, Tomoko Sao, Shinichiro Ochi, Jun-Ichi Iga, Shu-Ichi Ueno
AIM: It is difficult to diagnose dementia with Lewy bodies (DLB) because it exhibits clinical and neuropathological overlap with both Alzheimer's disease (AD) and Parkinson's disease (PD). The α-synuclein protein is a major component of Lewy bodies, and accumulation of α-synuclein aggregates causes synaptic dysfunction in DLB. Epigenetic changes at the synuclein alpha gene (SNCA) may be involved in DLB pathogenesis. METHODS: We examined DNA methylation rates at 10 CpG sites located in intron 1 of SNCA and SNCA mRNA expression in peripheral leukocytes to compare DLB patients (n = 20; 9 males, 11 females; age = 78...
September 29, 2016: Psychiatry and Clinical Neurosciences
Nóra Török, Zsófia Majláth, Levente Szalárdy, László Vécsei
The therapeutic management of Parkinson's disease (PD) is challenging and has not been fully resolved. The main challenges include motor fluctuations and levodopa-induced dyskinesia. Moreover, no disease-modifying or neuroprotective therapy is currently available. Areas covered: This review focuses on α-synuclein aggregation inhibitors and their therapeutic role in PD, with special attention to heat shock proteins, immunotherapy (active and passive), the potential of targeting the Ser129 phosphorylation site, and the antibiotic possibilities...
October 8, 2016: Expert Opinion on Investigational Drugs
Marija Iljina, Laura Tosatto, Minee L Choi, Jason C Sang, Yu Ye, Craig D Hughes, Clare E Bryant, Sonia Gandhi, David Klenerman
The protein alpha-synuclein (αS) self-assembles into toxic beta-sheet aggregates in Parkinson's disease, while it is proposed that αS forms soluble alpha-helical multimers in healthy neurons. Here, we have made αS multimers in vitro using arachidonic acid (ARA), one of the most abundant fatty acids in the brain, and characterized them by a combination of bulk experiments and single-molecule Fӧrster resonance energy transfer (sm-FRET) measurements. The data suggest that ARA-induced oligomers are alpha-helical, resistant to fibril formation, more prone to disaggregation, enzymatic digestion and degradation by the 26S proteasome, and lead to lower neuronal damage and reduced activation of microglia compared to the oligomers formed in the absence of ARA...
September 27, 2016: Scientific Reports
Alana Hoffmann, Benjamin Ettle, Ariane Bruno, Anna Kulinich, Anna-Carin Hoffmann, Julia von Wittgenstein, Jürgen Winkler, Wei Xiang, Johannes C M Schlachetzki
Synucleinopathies such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) are defined by the presence of intracellular alpha-synuclein aggregates in neurons and/or oligodendrocytes. In addition, post mortem tissue analysis revealed profound changes in microglial morphology, indicating microglial activation and neuroinflammation. Thus, alpha-synuclein may directly activate microglia, leading to increased production of key pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β), which in turn modulates the disease progression...
October 28, 2016: Biochemical and Biophysical Research Communications
Sara D Reis, Brígida R Pinho, Jorge M A Oliveira
Polyglutamine expansion mutations in specific proteins underlie the pathogenesis of a group of progressive neurodegenerative disorders, including Huntington's disease, spinal and bulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, and several spinocerebellar ataxias. The different mutant proteins share ubiquitous expression and abnormal proteostasis, with misfolding and aggregation, but nevertheless evoke distinct patterns of neurodegeneration. This highlights the relevance of the full protein context where the polyglutamine expansion occurs and suggests different interactions with the cellular proteostasis machinery...
September 22, 2016: Molecular Neurobiology
Anne-Gaëlle Corbillé, Michel Neunlist, Pascal Derkinderen
Since the observation that aggregated α-synuclein, the pathological hallmark of Parkinson's disease (PD), is found in the gut in almost all patients, it has been suggested that the enteric nervous system (ENS) could be a starting point for α-synuclein pathology. α-synuclein has long been thought to occur as a monomer in living cells, but recent studies reported that it instead exists as a tetramer in non-neuronal cells and in neurons. Given the possible key role of the ENS in PD pathophysiology, we undertook the current research to characterize the native state of α-synuclein in rat primary culture of ENS and in adult human healthy ENS...
September 17, 2016: Journal of Neurochemistry
Hongjun Xie, Jie Wu
Silica nanoparticles (SiO2-NPs) are widely applied in diagnosis, imaging, and drug delivery of central nervous diseases. Previously, we found that SiO2-NPs enter the brain and, more specifically, the dopaminergic neurons in the striatum. Whether SiO2-NPs have neurotoxicity and contribute to development of Parkinson's disease (PD) remains unclear. In this study, we investigated the effect of SiO2-NPs on PC12 cells, a dopaminergic neuron-like cell line. We showed that SiO2-NPs up-regulated α-synuclein expression, and N-acetyl cysteine reduced α-synuclein...
October 25, 2016: Chemico-biological Interactions
C Pellegrini, R Colucci, L Antonioli, E Barocelli, V Ballabeni, N Bernardini, C Blandizzi, W J de Jonge, M Fornai
BACKGROUND: Symptoms of digestive dysfunction in patients with Parkinson's disease (PD) occur at all stages of the disease, often preceding the onset of central motor symptoms. On the basis of these PD-preceding symptoms it has been proposed that PD could initiate in the gut, and that the presence of alpha-synuclein aggregates, or Lewy bodies in the enteric nervous system might represent one of the earliest signs of the disease. Following this hypothesis, much research has been focused on the digestive tract to unravel the mechanisms underlying the onset and progression of PD, with particular attention to the role of alterations in enteric neurotransmission in the pathophysiology of intestinal motility disturbances...
September 9, 2016: Neurogastroenterology and Motility: the Official Journal of the European Gastrointestinal Motility Society
Lingjia Xu, Jiali Pu
Parkinson's disease is a neurodegenerative disease/synucleinopathy that develops slowly; however, there is no efficient method of early diagnosis, nor is there a cure. Progressive dopaminergic neuronal cell loss in the substantia nigra pars compacta and widespread aggregation of the α-synuclein protein (encoded by the SNCA gene) in the form of Lewy bodies and Lewy neurites are the neuropathological hallmarks of Parkinson's disease. The SNCA gene has undergone gene duplications, triplications, and point mutations...
2016: Parkinson's Disease
Dan Luo, Horrick Sharma, Deepthi Yedlapudi, Tamara Antonio, Maarten E A Reith, Aloke K Dutta
Our ongoing drug development endeavor to design compounds for symptomatic and neuroprotective treatment of Parkinson's disease (PD) led us to carry out a structure activity relationship study based on dopamine agonists pramipexole and 5-OHDPAT. Our goal was to incorporate structural elements in these agonists in a way to preserve their agonist activity while producing inhibitory activity against aggregation of α-synuclein protein. In our design we appended various catechol and related phenol derivatives to the parent agonists via different linker lengths...
November 1, 2016: Bioorganic & Medicinal Chemistry
Dezerae Cox, Emily Selig, Michael D W Griffin, John A Carver, Heath Ecroyd
The aggregation of α-synuclein (α-syn) into amyloid fibrils is associated with neurodegenerative diseases, collectively referred to as the α-synucleinopathies. In vivo, molecular chaperones, such as the small heat-shock proteins (sHsps), normally act to prevent protein aggregation; however, it remains to be determined how aggregation-prone α-syn evades sHsp chaperone action leading to its disease-associated deposition. This work examines the molecular mechanism by which two canonical sHsps, αB-crystallin (αB-c) and Hsp27, interact with aggregation-prone α-syn to prevent its aggregation in vitro...
September 1, 2016: Journal of Biological Chemistry
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