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https://www.readbyqxmd.com/read/28934392/nceh-1-modulates-cholesterol-metabolism-and-protects-against-%C3%AE-synuclein-toxicity-in-a-c-elegans-model-of-parkinson-s-disease
#1
Siyuan Zhang, Samantha A Glukhova, Kim A Caldwell, Guy A Caldwell
Parkinson's disease (PD) is an aging-associated neurodegenerative disease affecting millions worldwide. Misfolding, oligomerization and accumulation of the human α-synuclein protein is a key pathological hallmark of PD and is associated with the progressive loss of dopaminergic neurons over the course of aging. Lifespan extension via the suppression of IGF-1/insulin-like signaling (IIS) offers a possibility to retard disease onset through induction of metabolic changes that provide neuroprotection. The nceh-1 gene of Caenorhabditis elegans encodes an ortholog of neutral cholesterol ester hydrolase 1 (NCEH-1), an IIS downstream protein that was identified in a screen as a modulator of α-synuclein accumulation in vivo...
October 1, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28933786/pink1-interacts-with-%C3%AE-synuclein-and-abrogates-%C3%AE-synuclein-induced-neurotoxicity-by-activating-autophagy
#2
Jia Liu, Xue Wang, Yongquan Lu, Chunli Duan, Ge Gao, Lingling Lu, Hui Yang
Parkinson's disease (PD) is one of the most common neurodegenerative diseases, characterized by degeneration of dopaminergic neurons in the substantia nigra. α-synuclein (α-syn) and PTEN-induced putative kinase (PINK)1 are two critical proteins associated with the pathogenesis of PD. α-syn induces mitochondrial deficits and apoptosis, PINK1 was found to alleviate α-syn-induced toxicity, but the mechanistic details remain obscure. Here, we show that PINK1 interacts with α-syn mainly in the cytoplasm, where it initiates autophagy...
September 21, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28933595/phosphoproteome-based-kinase-activity-profiling-reveals-the-critical-role-of-map2k2-and-plk1-in-neuronal-autophagy
#3
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/28931065/chlamydomonas-fap265-is-a-tubulin-polymerization-promoting-protein-essential-for-flagellar-reassembly-and-hatching-of-daughter-cells-from-the-sporangium
#4
Damayanti Tammana, Trinadh Venkata Satish Tammana
Tubulin polymerization promoting proteins (TPPPs) belong to a family of neomorphic moon lighting proteins, involved in various physiological and pathological conditions. In physiological conditions, TPPPs play an important role in microtubule dynamics regulating mitotic spindle assembly and in turn cell proliferation. In pathological situations, TPPPs interact with α-synuclein and β-amyloid and promote their aggregation leading to Parkinson's disease and multiple system atrophy. Orthologs of TPPP family proteins were identified in ciliary proteomes from various organisms including Chlamydomonas but their role in ciliogenesis was not known...
2017: PloS One
https://www.readbyqxmd.com/read/28928962/current-concepts-and-controversies-in-the-pathogenesis-of-parkinson-s-disease-dementia-and-dementia-with-lewy-bodies
#5
REVIEW
Rimona S Weil, Tammaryn L Lashley, Jose Bras, Anette E Schrag, Jonathan M Schott
Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) are relentlessly progressive neurodegenerative disorders that are likely to represent two ends of a disease spectrum. It is well established that both are characterised pathologically by widespread cortical Lewy body deposition. However, until recently, the pathophysiological mechanisms leading to neuronal damage were not known. It was also not understood why some cells are particularly vulnerable in PDD/DLB, nor why some individuals show more aggressive and rapid dementia than others...
2017: F1000Research
https://www.readbyqxmd.com/read/28928732/facile-affinity-maturation-of-antibody-variable-domains-using-natural-diversity-mutagenesis
#6
Kathryn E Tiller, Ratul Chowdhury, Tong Li, Seth D Ludwig, Sabyasachi Sen, Costas D Maranas, Peter M Tessier
The identification of mutations that enhance antibody affinity while maintaining high antibody specificity and stability is a time-consuming and laborious process. Here, we report an efficient methodology for systematically and rapidly enhancing the affinity of antibody variable domains while maximizing specificity and stability using novel synthetic antibody libraries. Our approach first uses computational and experimental alanine scanning mutagenesis to identify sites in the complementarity-determining regions (CDRs) that are permissive to mutagenesis while maintaining antigen binding...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28928221/upregulation-of-autophagy-related-gene-5-protects-dopaminergic-neurons-in-a-zebrafish-model-of-parkinson-s-disease
#7
Zhan-Ying Hu, Bo Chen, Jing-Pu Zhang, Yuan-Yuan Ma
Parkinson's disease (PD) is one of the most epidemic neurodegenerative diseases, and is characterized by movement disorders arising from loss of midbrain dopaminergic (DA) neurons. Recently, the relationship between PD and autophagy has received considerable attention, but information about the mechanisms involved is lacking. Here, we report that autophagy-related gene 5 (ATG5) is potentially important in protecting dopaminergic neurons in a 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model in zebrafish...
September 19, 2017: Journal of Biological Chemistry
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
#8
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
#9
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
#10
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/28923294/fundamental-limit-of-alpha-synuclein-pathology-in-gastrointestinal-biopsy-as-a-pathologic-biomarker-of-parkinson-s-disease-comparison-with-surgical-specimens
#11
Chaewon Shin, Sung-Hye Park, Ji Young Yun, Jung Hwan Shin, Han-Kwang Yang, Hyuk-Joon Lee, Seong-Ho Kong, Yun-Suhk Suh, Guangxun Shen, Yoon Kim, Han-Joon Kim, Beomseok Jeon
OBJECTIVE: Alpha-synuclein (AS) accumulation identified by immunohistochemistry (IHC) of gastrointestinal (GI) tract biopsies is considered as a potential pathologic biomarker for Parkinson's disease (PD). We compared AS IHC findings in biopsy specimens and surgically resected full-depth specimens to examine the reliability of GI tract biopsies. METHODS: We included patients with PD who had undergone operation of the GI tract for treatment of tumors. Controls were matched with age at operation, gender, and surgical resection site...
September 4, 2017: Parkinsonism & related Disorders
https://www.readbyqxmd.com/read/28922400/protein-folding-misfolding-and-aggregation-the-importance-of-two-electron-stabilizing-interactions
#12
Andrzej Stanisław Cieplak
Proteins associated with neurodegenerative diseases are highly pleiomorphic and may adopt an all-α-helical fold in one environment, assemble into all-β-sheet or collapse into a coil in another, and rapidly polymerize in yet another one via divergent aggregation pathways that yield broad diversity of aggregates' morphology. A thorough understanding of this behaviour may be necessary to develop a treatment for Alzheimer's and related disorders. Unfortunately, our present comprehension of folding and misfolding is limited for want of a physicochemical theory of protein secondary and tertiary structure...
2017: PloS One
https://www.readbyqxmd.com/read/28921554/dj-1-deficiency-impairs-autophagy-and-reduces-alpha-synuclein-phagocytosis-by-microglia
#13
Yuval Nash, Eran Schmukler, Dorit Trudler, Ronit Pinkas-Kramarski, Dan Frenkel
Parkinson's disease (PD) is a progressive neurodegenerative disorder, of which 1% of the hereditary cases are linked to mutations in DJ-1, an oxidative stress sensor. The pathological hallmark of PD is intercellular inclusions termed Lewy Bodies, composed mainly of α-Synuclein (α-Syn) protein. Recent findings have shown that α-Syn can be transmitted from cell to cell, suggesting an important role of microglia, as the main scavenger cells of the brain, in clearing α-Syn. We previously reported that the knock down (KD) of DJ-1 in microglia increased cells' neurotoxicity to dopaminergic neurons...
September 16, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28920936/dopamine-induces-soluble-%C3%AE-synuclein-oligomers-and-nigrostriatal-degeneration
#14
Danielle E Mor, Elpida Tsika, Joseph R Mazzulli, Neal S Gould, Hanna Kim, Malcolm J Daniels, Shachee Doshi, Preetika Gupta, Jennifer L Grossman, Victor X Tan, Robert G Kalb, Kim A Caldwell, Guy A Caldwell, John H Wolfe, Harry Ischiropoulos
Parkinson's disease (PD) is defined by the loss of dopaminergic neurons in the substantia nigra and the formation of Lewy body inclusions containing aggregated α-synuclein. Efforts to explain dopamine neuron vulnerability are hindered by the lack of dopaminergic cell death in α-synuclein transgenic mice. To address this, we manipulated both dopamine levels and α-synuclein expression. Nigrally targeted expression of mutant tyrosine hydroxylase with enhanced catalytic activity increased dopamine levels without damaging neurons in non-transgenic mice...
September 18, 2017: Nature Neuroscience
https://www.readbyqxmd.com/read/28919642/membrane-binding-of-parkinson-s-protein-%C3%AE-synuclein-effect-of-phosphorylation-at-positions-87-and-129-by-the-s-to-d-mutation-approach
#15
Pravin Kumar, Nathalie Schilderink, Vinod Subramaniam, Martina Huber
Human α-synuclein, a protein relevant in the brain with so-far unknown function, plays an important role in Parkinson's disease. The phosphorylation state of αS was related to the disease, prompting interest in this process. The presumed physiological function and the disease action of αS involves membrane interaction. Here, we study the effect of phosphorylation at positions 87 and 129, mimicked by the mutations S87A, S129A (nonphosphorylated) and S87D, S129D (phosphorylated) on membrane binding. Local binding is detected by spin-label continuous-wave electron paramagnetic resonance...
July 2017: Israel Journal of Chemistry
https://www.readbyqxmd.com/read/28918943/vagus-nerve-stimulation-improves-locomotion-and-neuronal-populations-in-a-model-of-parkinson-s-disease
#16
Ariana Q Farrand, Kristi L Helke, Rebecca A Gregory, Monika Gooz, Vanessa K Hinson, Heather A Boger
BACKGROUND: Parkinson's disease (PD) is a progressive, neurodegenerative disorder with no disease-modifying therapies, and symptomatic treatments are often limited by debilitating side effects. In PD, locus coeruleus noradrenergic (LC-NE) neurons degenerate prior to substantia nigra dopaminergic (SN-DA) neurons. Vagus nerve stimulation (VNS) activates LC neurons, and decreases pro-inflammatory markers, allowing improvement of LC targets, making it a potential PD therapeutic. OBJECTIVE: To assess therapeutic potential of VNS in a PD model...
August 24, 2017: Brain Stimulation
https://www.readbyqxmd.com/read/28918129/where-do-substrates-of-diacylglycerol-kinases-come-from-diacylglycerol-kinases-utilize-diacylglycerol-species-supplied-from-phosphatidylinositol-turnover-independent-pathways
#17
REVIEW
Fumio Sakane, Satoru Mizuno, Daisuke Takahashi, Hiromichi Sakai
Diacylglycerol kinase (DGK) phosphorylates diacylglycerol (DG) to produce phosphatidic acid (PA). Mammalian DGK comprises ten isozymes (α-κ) and regulates a wide variety of physiological and pathological events, such as cancer, type II diabetes, neuronal disorders and immune responses. DG and PA consist of various molecular species that have different acyl chains at the sn-1 and sn-2 positions, and consequently, mammalian cells contain at least 50 structurally distinct DG/PA species. Because DGK is one of the components of phosphatidylinositol (PI) turnover, the generally accepted dogma is that all DGK isozymes utilize 18:0/20:4-DG derived from PI turnover...
September 9, 2017: Advances in Biological Regulation
https://www.readbyqxmd.com/read/28918091/opposed-effects-of-dityrosine-formation-in-soluble-and-aggregated-%C3%AE-synuclein-on-fibril-growth
#18
Michael M Wördehoff, Hamed Shaykhalishahi, Luca Groß, Lothar Gremer, Matthias Stoldt, Alexander K Buell, Dieter Willbold, Wolfgang Hoyer
Parkinson's disease (PD) is the second most common neurodegenerative disease. It is characterized by aggregation of the protein α-synuclein (α-syn) in Lewy bodies, mitochondrial dysfunction, and increased oxidative stress in the substantia nigra. Oxidative stress leads to several modifications of biomolecules including dityrosine (DiY)-crosslinking in proteins, which has recently been detected in α-syn in Lewy bodies from PD patients. Here we report that α-syn is highly susceptible to UV-induced DiY formation...
September 13, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28918051/lrrk2-antisense-oligonucleotides-ameliorate-%C3%AE-synuclein-inclusion-formation-in-a-parkinson-s-disease-mouse-model
#19
Hien Tran Zhao, Neena John, Vedad Delic, Karli Ikeda-Lee, Aneeza Kim, Andreas Weihofen, Eric E Swayze, Holly B Kordasiewicz, Andrew B West, Laura A Volpicelli-Daley
No treatments exist to slow or halt Parkinson's disease (PD) progression; however, inhibition of leucine-rich repeat kinase 2 (LRRK2) activity represents one of the most promising therapeutic strategies. Genetic ablation and pharmacological LRRK2 inhibition have demonstrated promise in blocking α-synuclein (α-syn) pathology. However, LRRK2 kinase inhibitors may reduce LRRK2 activity in several tissues and induce systemic phenotypes in the kidney and lung that are undesirable. Here, we test whether antisense oligonucleotides (ASOs) provide an alternative therapeutic strategy, as they can be restricted to the CNS and provide a stable, long-lasting reduction of protein throughout the brain...
September 15, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28914525/two-distinct-polymorphic-folding-states-of-self-assembly-of-the-non-amyloid-%C3%AE-component-differ-in-the-arrangement-of-the-residues
#20
Maya Pollock-Gagolashvili, Yifat Miller
Parkinson's disease is a degenerative disorder of the central nerves system. It is characterized by presence of Lew bodies (LBs), in which the main components of the LBs are α-synuclein (AS) aggregates. The central domain of AS, known as the "non-amyloid β component" (NAC) is responsible for the aggregation properties of AS. It is proposed that AS fibrillar structure is a well-packed cross-β structure of the NAC domains, while the N- and C-termini are disordered. Therefore, the study of the self-assembly of NAC domains are crucial in order to understand the molecular mechanisms of AS aggregation...
September 15, 2017: ACS Chemical Neuroscience
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