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alpha synuclein and aggregation

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https://www.readbyqxmd.com/read/28933595/phosphoproteome-based-kinase-activity-profiling-reveals-the-critical-role-of-map2k2-and-plk1-in-neuronal-autophagy
#1
Lei-Lei Chen, Yong-Bo Wang, Ju-Xian Song, Wan-Kun Deng, Jia-Hong Lu, Li-Li Ma, Chuan-Bin Yang, Min Li, Yu Xue
Recent studies have demonstrated that dysregulation of macroautophagy/autophagy may play a central role in the pathogenesis of neurodegenerative disorders, and the induction of autophagy protects against the toxic insults of aggregate-prone proteins by enhancing their clearance. Thus, autophagy has become a promising therapeutic target against neurodegenerative diseases. In this study, quantitative phosphoproteomic profiling together with a computational analysis was performed to delineate the phosphorylation signalling networks regulated by 2 natural neuroprotective autophagy enhancers, corynoxine (Cory) and corynoxine B (Cory B)...
September 21, 2017: Autophagy
https://www.readbyqxmd.com/read/28927576/loss-of-microrna-7-regulation-leads-to-%C3%AE-synuclein-accumulation-and-dopaminergic-neuronal-loss-in%C3%A2-vivo
#2
Kirsty J McMillan, Tracey K Murray, Nora Bengoa-Vergniory, Oscar Cordero-Llana, Jane Cooper, Amy Buckley, Richard Wade-Martins, James B Uney, Michael J O'Neill, Liang F Wong, Maeve A Caldwell
Abnormal alpha-synuclein (α-synuclein) expression and aggregation is a key characteristic of Parkinson's disease (PD). However, the exact mechanism(s) linking α-synuclein to the other central feature of PD, dopaminergic neuron loss, remains unclear. Therefore, improved cell and in vivo models are needed to investigate the role of α-synuclein in dopaminergic neuron loss. MicroRNA-7 (miR-7) regulates α-synuclein expression by binding to the 3' UTR of the Synuclein Alpha Non A4 Component of Amyloid Precursor (SNCA) gene and inhibiting its translation...
August 31, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28924920/age-dependent-alpha-synuclein-accumulation-and-phosphorylation-in-the-enteric-nervous-system-in-a-transgenic-mouse-model-of-parkinson-s-disease
#3
Chong-Bin Zhong, Qian-Qian Chen, Caroline Haikal, Wen Li, Alexander Svanbergsson, Meike Diepenbroek, Jia-Yi Li
The enteric nervous system (ENS) controls the function of the gastrointestinal tract and has been implicated in various diseases, including Parkinson's disease (PD). PD is a neurodegenerative disease with Lewy bodies (LBs) and Lewy neurites (LNs) as the main pathological features. In addition to the typical motor symptoms in PD, attention has been drawn to non-motor symptoms, such as constipation, implying dysfunction of the ENS. In the present study, we characterized the age-dependent morphological alterations and aggregation of α-synuclein (α-syn), the primary protein component in LBs and LNs, in the ENS in an α-syn transgenic mouse model...
September 18, 2017: Neuroscience Bulletin
https://www.readbyqxmd.com/read/28923922/trkb-neurotrophic-activities-are-blocked-by-%C3%AE-synuclein-triggering-dopaminergic-cell-death-in-parkinson-s-disease
#4
Seong Su Kang, Zhentao Zhang, Xia Liu, Fredric P Manfredsson, Matthew J Benskey, Xuebing Cao, Jun Xu, Yi E Sun, Keqiang Ye
BDNF/TrkB neurotrophic signaling is essential for dopaminergic neuronal survival, and the activities are reduced in the substantial nigra (SN) of Parkinson's disease (PD). However, whether α-Syn (alpha-synuclein) aggregation, a hallmark in the remaining SN neurons in PD, accounts for the neurotrophic inhibition remains elusive. Here we show that α-Syn selectively interacts with TrkB receptors and inhibits BDNF/TrkB signaling, leading to dopaminergic neuronal death. α-Syn binds to the kinase domain on TrkB, which is negatively regulated by BDNF or Fyn tyrosine kinase...
September 18, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28900170/protein-arginylation-targets-alpha-synuclein-facilitates-normal-brain-health-and-prevents-neurodegeneration
#5
Junling Wang, Xuemei Han, Nicolae Adrian Leu, Stephanie Sterling, Satoshi Kurosaka, Marie Fina, Virginia M Lee, Dawei W Dong, John R Yates, Anna Kashina
Alpha synuclein (α-syn) is a central player in neurodegeneration, but the mechanisms triggering its pathology are not fully understood. Here we found that α-syn is a highly efficient substrate for arginyltransferase ATE1 and is arginylated in vivo by a novel mid-chain mechanism that targets the acidic side chains of E46 and E83. Lack of arginylation leads to increased α-syn aggregation and causes the formation of larger pathological aggregates in neurons, accompanied by impairments in its ability to be cleared via normal degradation pathways...
September 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28874699/metal-concentrations-and-distributions-in-the-human-olfactory-bulb-in-parkinson-s-disease
#6
Bronwen Gardner, Birger V Dieriks, Steve Cameron, Lakshini H S Mendis, Clinton Turner, Richard L M Faull, Maurice A Curtis
In Parkinson's disease (PD), the olfactory bulb is typically the first region in the body to accumulate alpha-synuclein aggregates. This pathology is linked to decreased olfactory ability, which becomes apparent before any motor symptoms occur, and may be due to a local metal imbalance. Metal concentrations were investigated in post-mortem olfactory bulbs and tracts from 17 human subjects. Iron (p < 0.05) and sodium (p < 0.01) concentrations were elevated in the PD olfactory bulb. Combining laser ablation inductively coupled plasma mass spectrometry and immunohistochemistry, iron and copper were evident at very low levels in regions of alpha-synuclein aggregation...
September 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28866688/alpha-synuclein-to-the-rescue-immune-cell-recruitment-by-alpha-synuclein-during-gastrointestinal-infection
#7
Viviane Labrie, Patrik Brundin
Intraneuronal accumulation of misfolded alpha-synuclein in the central and peripheral nervous systems is strongly linked to Parkinson disease (PD) and other related synucleinopathies. In rare inherited forms of PD, point mutations or gene multiplications mediate the formation of alpha-synuclein protein aggregates. However, in most PD cases it is presumed that the combined effects of ageing and environmental factors drive the formation of alpha-synuclein aggregates. Despite advances regarding alpha-synuclein pathobiology, the normal functions of this protein and factors that regulate its expression are not well understood...
2017: Journal of Innate Immunity
https://www.readbyqxmd.com/read/28863169/effects-of-small-molecule-amyloid-modulators-on-a-drosophila-model-of-parkinson-s-disease
#8
Małgorzata Pokrzywa, Katarzyna Pawełek, Weronika Elżbieta Kucia, Szymon Sarbak, Erik Chorell, Fredrik Almqvist, Pernilla Wittung-Stafshede
Alpha-synuclein (aS) amyloid formation is involved in Parkinson's disease (PD); therefore, small molecules that target aS and affect its aggregation are of interest as future drug candidates. We recently reported modified ring-fused 2-pyridones that modulate aS amyloid formation in vitro. Here, we describe the effects of such molecules on behavioral parameters of a Drosophila model of PD (i.e., flies expressing human aS), using a new approach (implemented in a commercially available FlyTracker system) to quantify fly mobility...
2017: PloS One
https://www.readbyqxmd.com/read/28841377/role-of-sporadic-parkinson-disease-associated-mutations-a18t-and-a29s-in-enhanced-%C3%AE-synuclein-fibrillation-and-cytotoxicity
#9
Sanjay Kumar, Deepak Kumar Jangir, Roshan Kumar, Manisha Kumari, Neel Sarovar Bhavesh, Tushar Kanti Maiti
Deposition of presynaptic protein α-synuclein in Lewy bodies and Lewy neurites in the substantia nigra region of brain has been linked with the clinical symptoms of the Parkinson's disease (PD). Proteotoxic stress conditions and mutations that cause abnormal aggregation of α-synuclein have close association with onset of PD and its progression. Therefore, studies pertaining to α-synuclein mutations play important roles in mechanistic understanding of aggregation behavior of the protein and subsequent pathology...
September 6, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28835999/glucocerebrosidase-expression-patterns-in-the-non-human-primate-brain
#10
Iria G Dopeso-Reyes, Diego Sucunza, Alberto J Rico, Diego Pignataro, David Marín-Ramos, Elvira Roda, Ana I Rodríguez-Pérez, José L Labandeira-García, José L Lanciego
Glucocerebrosidase (GCase) is a lysosomal enzyme encoded by the GBA1 gene. Mutations in GBA1 gene lead to Gaucher's disease, the most prevalent lysosomal storage disorder. GBA1 mutations reduce GCase activity, therefore promoting the aggregation of alpha-synuclein, a common neuropathological finding underlying Parkinson's disease (PD) and dementia with Lewy bodies. However, it is also worth noting that a direct link between GBA1 mutations and alpha-synuclein aggregation indicating cause and effect is still lacking, with limited experimental evidence to date...
August 23, 2017: Brain Structure & Function
https://www.readbyqxmd.com/read/28827536/cellular-internalization-of-alpha-synuclein-aggregates-by-cell-surface-heparan-sulfate-depends-on-aggregate-conformation-and-cell-type
#11
Elisabet Ihse, Hodaka Yamakado, Xander M van Wijk, Roger Lawrence, Jeffrey D Esko, Eliezer Masliah
Amyloid aggregates found in the brain of patients with neurodegenerative diseases, including Alzheimer's and Parkinson's disease, are thought to spread to increasingly larger areas of the brain through a prion-like seeding mechanism. Not much is known about which cell surface receptors may be involved in the cell-to-cell transfer, but proteoglycans are of interest due to their well-known propensity to interact with amyloid aggregates. In this study, we investigated the involvement of plasma membrane-bound heparan and chondroitin sulfate proteoglycans in cellular uptake of aggregates consisting of α-synuclein, a protein forming amyloid aggregates in Parkinson's disease...
August 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28826526/small-molecule-pet-tracers-for-imaging-proteinopathies
#12
REVIEW
Chester A Mathis, Brian J Lopresti, Milos D Ikonomovic, William E Klunk
In this chapter, we provide a review of the challenges and advances in developing successful PET imaging agents for 3 major types of aggregated amyloid proteins: amyloid-beta (Aβ), tau, and alpha-synuclein (α-syn). These 3 amyloids are involved in the pathogenesis of a variety of neurodegenerative diseases, referred to as proteinopathies or proteopathies, that include Alzheimer disease, Lewy body dementias, multiple system atrophy, and frontotemporal dementias, among others. In the Introduction section, we briefly discuss the history of amyloid in neurodegenerative diseases and describe why progress in developing effective imaging agents has been hampered by the failure of crystallography to provide definitive ligand-protein interactions for rational radioligand design efforts...
September 2017: Seminars in Nuclear Medicine
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
#13
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
#14
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/28803148/combustion-derived-nanoparticles-the-neuroenteric-system-cervical-vagus-hyperphosphorylated-alpha-synuclein-and-tau-in-young-mexico-city-residents
#15
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/28797124/preclinical-development-of-a-vaccine-against-oligomeric-alpha-synuclein-based-on-virus-like-particles
#16
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
#17
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
#18
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/28780169/the-pmr1-pump-in-alpha-synuclein-toxicity-and-neurodegeneration
#19
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/28763613/the-importance-of-mitophagy-in-maintaining-mitochondrial-function-in-u373mg-cells-bafilomycin-a1-restores-aminochrome-induced-mitochondrial-damage
#20
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
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