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Alpha-synuclein

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https://www.readbyqxmd.com/read/28821274/candidate-inflammatory-biomarkers-display-unique-relationships-with-alpha-synuclein-and-correlate-with-measures-of-disease-severity-in-subjects-with-parkinson-s-disease
#1
Lori N Eidson, George T Kannarkat, Christopher J Barnum, Jianjun Chang, Jaegwon Chung, Chelsea Caspell-Garcia, Peggy Taylor, Brit Mollenhauer, Michael G Schlossmacher, Larry Ereshefsky, Mark Yen, Catherine Kopil, Mark Frasier, Kenneth Marek, Vicki S Hertzberg, Malú G Tansey
BACKGROUND: Efforts to identify fluid biomarkers of Parkinson's disease (PD) have intensified in the last decade. As the role of inflammation in PD pathophysiology becomes increasingly recognized, investigators aim to define inflammatory signatures to help elucidate underlying mechanisms of disease pathogenesis and aid in identification of patients with inflammatory endophenotypes that could benefit from immunomodulatory interventions. However, discordant results in the literature and a lack of information regarding the stability of inflammatory factors over a 24-h period have hampered progress...
August 18, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/28811225/alpha-synuclein-ferrireductase-activity-is-detectible-in-vivo-is-altered-in-parkinson-s-disease-and-increases-the-neurotoxicity-of-dopal
#2
Jennifer S McDowall, Ioanna Ntai, Kevin C Honeychurch, John P Hart, Philippe Colin, Bernard L Schneider, David R Brown
The normal cellular role of α-synuclein is of potential importance in understanding diseases in which an aggregated form of the protein has been implicated. A potential loss or change in the normal function of α-synuclein could play a role in the aetiology of diseases such as Parkinson's disease. Recently, it has been suggested that α-synuclein could cause the enzymatic reduction of iron and a cellular increase in Fe(II) levels. Experiments were carried out to determine if such activity could be measured in vivo...
August 12, 2017: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/28808780/non-cns-pathogenic-origin-of-parkinson-s-disease
#3
Humdoon Choudhry, Lawrence C Perlmuter
The gut with its variety of microbiota may serve as an etiological origin of diseases. Gut microbes may also play a role in the pathogenesis of diseases beyond their simple nutritional maintenance and support. For example, gut protein aggregation, possibly aided by microbes as well as nasal influences, might be linked to disease that may move to the brain through the vagus nerve. To this end, Braak has offered a "dual-hit" hypothesis that proposes a novel etiology for Parkinson's disease (PD). The hypothesis places the initial origin of the disease in the nose and the gastrointestinal tract (GI) after infection by an unknown pathogen that could aggregate in the gut and then eventually spread to the brain via the autonomic plexuses...
August 14, 2017: Journal of Neurology
https://www.readbyqxmd.com/read/28803412/alpha-synuclein-oligomers-a-new-hope
#4
REVIEW
Nora Bengoa-Vergniory, Rosalind F Roberts, Richard Wade-Martins, Javier Alegre-Abarrategui
Alpha-synuclein is a protein implicated in Parkinson's disease and thought to be one of the main pathological drivers in the disease, although it remains unclear how this protein elicits its neurotoxic effects. Recent findings indicate that the assembly of toxic oligomeric species of alpha-synuclein may be one of the key processes for the pathology and spread of the disease. The absence of a sensitive in situ detection method has hindered the study of these oligomeric species and the role they play in the human brain until recently...
August 12, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28803148/combustion-derived-nanoparticles-the-neuroenteric-system-cervical-vagus-hyperphosphorylated-alpha-synuclein-and-tau-in-young-mexico-city-residents
#5
Lilian Calderón-Garcidueñas, Rafael Reynoso-Robles, Beatriz Pérez-Guillé, Partha S Mukherjee, Angélica Gónzalez-Maciel
Mexico City (MC) young residents are exposed to high levels of fine particulate matter (PM2.5), have high frontal concentrations of combustion-derived nanoparticles (CDNPs), accumulation of hyperphosphorylated aggregated α-synuclein (α-Syn) and early Parkinson's disease (PD). Swallowed CDNPs have easy access to epithelium and submucosa, damaging gastrointestinal (GI) barrier integrity and accessing the enteric nervous system (ENS). This study is focused on the ENS, vagus nerves and GI barrier in young MC v clean air controls...
August 9, 2017: Environmental Research
https://www.readbyqxmd.com/read/28800113/biomarker-research-in-parkinson-s-disease-using-metabolite-profiling
#6
REVIEW
Jesper F Havelund, Niels H H Heegaard, Nils J K Færgeman, Jan Bert Gramsbergen
Biomarker research in Parkinson's disease (PD) has long been dominated by measuring dopamine metabolites or alpha-synuclein in cerebrospinal fluid. However, these markers do not allow early detection, precise prognosis or monitoring of disease progression. Moreover, PD is now considered a multifactorial disease, which requires a more precise diagnosis and personalized medication to obtain optimal outcome. In recent years, advanced metabolite profiling of body fluids like serum/plasma, CSF or urine, known as "metabolomics", has become a powerful and promising tool to identify novel biomarkers or "metabolic fingerprints" characteristic for PD at various stages of disease...
August 11, 2017: Metabolites
https://www.readbyqxmd.com/read/28797721/intact-blood-brain-barrier-transport-of-small-molecular-drugs-in-animal-models-of-amyloid-beta-and-alpha-synuclein-pathology
#7
Sofia Gustafsson, Veronica Lindström, Martin Ingelsson, Margareta Hammarlund-Udenaes, Stina Syvänen
Pathophysiological impairment of the neurovascular unit, including the integrity and dynamics of the blood-brain barrier (BBB), has been denoted both a cause and consequence of neurodegenerative diseases. Pathological impact on BBB drug delivery has also been debated. The aim of the present study was to investigate BBB drug transport, by determining the unbound brain-to-plasma concentration ratio (Kp,uu,brain), in aged AβPP-transgenic mice, α-synuclein transgenic mice, and wild type mice. Mice were dosed with a cassette of five compounds, including digoxin, levofloxacin (1 mg/kg, s...
August 5, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28797124/preclinical-development-of-a-vaccine-against-oligomeric-alpha-synuclein-based-on-virus-like-particles
#8
Marika Doucet, Aadil El-Turabi, Franziska Zabel, Benjamin H M Hunn, Nora Bengoa-Vergniory, Milena Cioroch, Mauricio Ramm, Amy M Smith, Ariane Cruz Gomes, Gustavo Cabral de Miranda, Richard Wade-Martins, Martin F Bachmann
Parkinson's disease (PD) is a progressive and currently incurable neurological disorder characterised by the loss of midbrain dopaminergic neurons and the accumulation of aggregated alpha-synuclein (a-syn). Oligomeric a-syn is proposed to play a central role in spreading protein aggregation in the brain with associated cellular toxicity contributing to a progressive neurological decline. For this reason, a-syn oligomers have attracted interest as therapeutic targets for neurodegenerative conditions such as PD and other alpha-synucleinopathies...
2017: PloS One
https://www.readbyqxmd.com/read/28794446/impaired-endo-lysosomal-membrane-integrity-accelerates-the-seeding-progression-of-%C3%AE-synuclein-aggregates
#9
Peizhou Jiang, Ming Gan, Shu-Hui Yen, Pamela J McLean, Dennis W Dickson
In neurodegenerative diseases, seeding is a process initiated by the internalization of exogenous protein aggregates. Multiple pathways for internalization of aggregates have been proposed, including direct membrane penetration and endocytosis. To decipher the seeding mechanisms of alpha-synuclein (αS) aggregates in human cells, we visualized αS aggregation, endo-lysosome distribution, and endo-lysosome rupture in real-time. Our data suggest that exogenous αS can seed endogenous cytoplasmic αS by either directly penetrating the plasma membrane or via endocytosis-mediated endo-lysosome rupture, leading to formation of endo-lysosome-free or endo-lysosome-associated αS aggregates, respectively...
August 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28790323/mitochondrial-division-inhibitor-1-is-neuroprotective-in-the-a53t-%C3%AE-synuclein-rat-model-of-parkinson-s-disease
#10
Simone Bido, Federico N Soria, Rebecca Z Fan, Erwan Bezard, Kim Tieu
Alpha-synuclein (α-syn) is involved in both familial and sporadic Parkinson's disease (PD). One of the proposed pathogenic mechanisms of α-syn mutations is mitochondrial dysfunction. However, it is not entirely clear the impact of impaired mitochondrial dynamics induced by α-syn on neurodegeneration and whether targeting this pathway has therapeutic potential. In this study we evaluated whether inhibition of mitochondrial fission is neuroprotective against α-syn overexpression in vivo. To accomplish this goal, we overexpressed human A53T-α- synuclein (hA53T-α-syn) in the rat nigrostriatal pathway, with or without treatment using the small molecule Mitochondrial Division Inhibitor-1 (mdivi-1), a putative inhibitor of the mitochondrial fission Dynamin-Related Protein-1 (Drp1)...
August 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28782845/alpha-synuclein-triggers-t-cell-response-is-parkinson-s-disease-an-autoimmune-disorder
#11
Sara Bandres-Ciga, Mark R Cookson
No abstract text is available yet for this article.
August 7, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28780169/the-pmr1-pump-in-alpha-synuclein-toxicity-and-neurodegeneration
#12
REVIEW
Vassiliki Nikoletopoulou, Nektarios Tavernarakis
Proteinopathies constitute a diverse group of devastating neurodegenerative disorders, characterized by aberrant aggregation of specific proteins within neurons and in the brain parenchyma. Parkinson's disease (PD) is among the most common proteinopathies, caused by the accumulation of different species of α-synuclein and the formation of protein inclusions known as Lewy bodies. Although several mutations in the α-synuclein gene have been linked to PD, the mechanisms mediating the aggregation and toxicity of α-synuclein are not fully understood...
August 2, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28776303/premotor-diagnosis-of-parkinson-s-disease
#13
REVIEW
Heinz Reichmann
Typical Parkinsonian symptoms consist of bradykinesia plus rigidity and/or resting tremor. Some time later postural instability occurs. Pre-motor symptoms such as hyposmia, constipation, REM sleep behavior disorder and depression may antecede these motor symptoms for years. It would be ideal, if we had a biomarker which would allow to predict who with one or two of these pre-motor symptoms will develop the movement disorder Parkinson's disease (PD). Thus, it is interesting to learn that biopsies of the submandibular gland or colon biopsies may be a means to predict PD, if there is a high amout of abnormally folded alpha-synuclein and phosphorylated alpha-synuclein...
August 3, 2017: Neuroscience Bulletin
https://www.readbyqxmd.com/read/28768533/progression-of-pathology-in-pink1-deficient-mouse-brain-from-splicing-via-ubiquitination-er-stress-and-mitophagy-changes-to-neuroinflammation
#14
Sylvia Torres-Odio, Jana Key, Hans-Hermann Hoepken, Júlia Canet-Pons, Lucie Valek, Bastian Roller, Michael Walter, Blas Morales-Gordo, David Meierhofer, Patrick N Harter, Michel Mittelbronn, Irmgard Tegeder, Suzana Gispert, Georg Auburger
BACKGROUND: PINK1 deficiency causes the autosomal recessive PARK6 variant of Parkinson's disease. PINK1 activates ubiquitin by phosphorylation and cooperates with the downstream ubiquitin ligase PARKIN, to exert quality control and control autophagic degradation of mitochondria and of misfolded proteins in all cell types. METHODS: Global transcriptome profiling of mouse brain and neuron cultures were assessed in protein-protein interaction diagrams and by pathway enrichment algorithms...
August 2, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/28763613/the-importance-of-mitophagy-in-maintaining-mitochondrial-function-in-u373mg-cells-bafilomycin-a1-restores-aminochrome-induced-mitochondrial-damage
#15
Sandro Huenchuguala, Patricia Muñoz, Juan Segura-Aguilar
Aminochrome, an orthoquinone formed during the dopamine oxidation of neuromelanin, is neurotoxic because it induces mitochondria dysfunction, protein degradation dysfunction (both autophagy and proteasomal systems), α-synuclein aggregation to neurotoxic oligomers, neuroinflammation, and oxidative and endoplasmic reticulum stress. In this study, we investigated the relationship between aminochrome-induced autophagy/lysosome dysfunction and mitochondrial dysfunction in U373MGsiGST6 cells. Aminochrome (75 μM) induces mitochondrial dysfunction as determined by (i) a significant decrease in ATP levels (70%; P < 0...
August 15, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28761417/on-the-role-of-endogenous-neurotoxins-and-neuroprotection-in-parkinson-s-disease
#16
REVIEW
Juan Segura-Aguilar
For 50 years ago was introduced L-3,4-dihydroxyphenylalanine (L-dopa) in Parkinson's disease treatment and during this significant advances has been done but what trigger the degeneration of the nigrostriatal system remain unknown. There is a general agreement in the scientific community that mitochondrial dysfunction, protein degradation dysfunction, alpha-synuclein aggregation to neurotoxic oligomers, neuroinflammation, oxidative and endoplasmic reticulum stress are involved in the loss of dopaminergic neurons containing neuromelanin in Parkinson's disease...
June 2017: Neural Regeneration Research
https://www.readbyqxmd.com/read/28741230/new-therapeutic-strategies-for-lewy-body-dementias
#17
REVIEW
Latha Velayudhan, Dominic Ffytche, Clive Ballard, Dag Aarsland
This article reviews current treatment strategies and recent advances for the Lewy body dementias (LBDs). Current available symptom treatment strategies are based on monoaminergic, cholinergic and glutaminergic neurotransmitter systems. Relatively robust evidence exists for cholinesterase inhibitors for cognitive impairment in LBD and in Parkinson's disease for antidepressants, clozapine and recently pimavanserin for psychosis. interpidine (RVT 101) and nelotanserin are currently under investigation. Non-pharmacological interventions, such as cognitive stimulation, physical exercises and neuromodulation strategies, may be useful in Parkinson's disease but have not yet been tested in dementias...
September 2017: Current Neurology and Neuroscience Reports
https://www.readbyqxmd.com/read/28736195/allelic-difference-in-mhc2ta-confers-altered-microglial-activation-and-susceptibility-to-%C3%AE-synuclein-induced-dopaminergic-neurodegeneration
#18
Itzia Jimenez-Ferrer, Michael Jewett, Ashmita Tontanahal, Marina Romero-Ramos, Maria Swanberg
Parkinson's Disease (PD) is a complex and heterogeneous neurodegenerative disease characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta and pathological intracellular accumulation of alpha-synuclein (α-syn). In the vast majority of PD patients, the disease has a complex etiology, defined by multiple genetic and environmental risk factors. Common genetic variants in the human leukocyte-antigen (HLA) region have been associated to PD risk and the carriage of these can double the risk to develop PD...
July 20, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28732710/cytokine-profiling-in-the-prefrontal-cortex-of-parkinson-s-disease-and-multiple-system-atrophy-patients
#19
Rasmus Rydbirk, Betina Elfving, Mille Dahl Andersen, Mia Aggergaard Langbøl, Jonas Folke, Kristian Winge, Bente Pakkenberg, Tomasz Brudek, Susana Aznar
Parkinson's Disease (PD) and Multiple System Atrophy (MSA) are neurodegenerative diseases characterized neuropathologically by alpha-synuclein accumulation in brain cells. This accumulation is hypothesized to contribute to constitutive neuroinflammation, and to participate in the neurodegeneration. Cytokines, which are the main inflammatory signalling molecules, have been identified in blood and cerebrospinal fluid of PD patients, but studies investigating the human brain levels are scarce. It is documented that neurotrophins, necessary for survival of brain cells and known to interact with cytokines, are altered in the basal ganglia of PD patients...
July 19, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28731447/chromatin-bound-oxidized-%C3%AE-synuclein-causes-strand-breaks-in-neuronal-genomes-in-in-vitro-models-of-parkinson-s-disease
#20
Velmarini Vasquez, Joy Mitra, Pavana M Hegde, Arvind Pandey, Shiladitya Sengupta, Sankar Mitra, K S Rao, Muralidhar L Hegde
Alpha-synuclein (α-Syn) overexpression and misfolding/aggregation in degenerating dopaminergic neurons have long been implicated in Parkinson's disease (PD). The neurotoxicity of α-Syn is enhanced by iron (Fe) and other pro-oxidant metals, leading to generation of reactive oxygen species in PD brain. Although α-Syn is predominantly localized in presynaptic nerve terminals, a small fraction exists in neuronal nuclei. However, the functional and/or pathological role of nuclear α-Syn is unclear. Following up on our earlier report that α-Syn directly binds DNA in vitro, here we confirm the nuclear localization and chromatin association of α-Syn in neurons using proximity ligation and chromatin immunoprecipitation analysis...
July 17, 2017: Journal of Alzheimer's Disease: JAD
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