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https://www.readbyqxmd.com/read/28096359/%C3%AE-synuclein-binds-and-sequesters-pike-l-into-lewy-bodies-triggering-dopaminergic-cell-death-via-ampk-hyperactivation
#1
Seong Su Kang, Zhentao Zhang, Xia Liu, Fredric P Manfredsson, Li He, P Michael Iuvone, Xuebing Cao, Yi E Sun, Lingjing Jin, Keqiang Ye
The abnormal aggregation of fibrillar α-synuclein in Lewy bodies plays a critical role in the pathogenesis of Parkinson's disease. However, the molecular mechanisms regulating α-synuclein pathological effects are incompletely understood. Here we show that α-synuclein binds phosphoinositide-3 kinase enhancer L (PIKE-L) in a phosphorylation-dependent manner and sequesters it in Lewy bodies, leading to dopaminergic cell death via AMP-activated protein kinase (AMPK) hyperactivation. α-Synuclein interacts with PIKE-L, an AMPK inhibitory binding partner, and this action is increased by S129 phosphorylation through AMPK and is decreased by Y125 phosphorylation via Src family kinase Fyn...
January 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28096355/a-natural-product-inhibits-the-initiation-of-%C3%AE-synuclein-aggregation-and-suppresses-its-toxicity
#2
Michele Perni, Céline Galvagnion, Alexander Maltsev, Georg Meisl, Martin B D Müller, Pavan K Challa, Julius B Kirkegaard, Patrick Flagmeier, Samuel I A Cohen, Roberta Cascella, Serene W Chen, Ryan Limboker, Pietro Sormanni, Gabriella T Heller, Francesco A Aprile, Nunilo Cremades, Cristina Cecchi, Fabrizio Chiti, Ellen A A Nollen, Tuomas P J Knowles, Michele Vendruscolo, Adriaan Bax, Michael Zasloff, Christopher M Dobson
The self-assembly of α-synuclein is closely associated with Parkinson's disease and related syndromes. We show that squalamine, a natural product with known anticancer and antiviral activity, dramatically affects α-synuclein aggregation in vitro and in vivo. We elucidate the mechanism of action of squalamine by investigating its interaction with lipid vesicles, which are known to stimulate nucleation, and find that this compound displaces α-synuclein from the surfaces of such vesicles, thereby blocking the first steps in its aggregation process...
January 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28090391/neurotoxin-induced-catecholaminergic-loss-in-the-colonic-myenteric-plexus-of-rhesus-monkeys
#3
Jeanette M Shultz, Henry Resnikoff, Viktorya Bondarenko, Valerie Joers, Andres Mejia, Heather Simmons, Marina E Emborg
OBJECTIVE: Constipation is a common non-motor symptom of Parkinson's disease (PD). Although pathology of the enteric nervous system (ENS) has been associated with constipation in PD, the contribution of catecholaminergic neurodegeneration to this symptom is currently debated. The goal of this study was to assess the effects of the neurotoxin 6-hydroxydopamine (6-OHDA) on the colonic myenteric plexus and shed light on the role of catecholaminergic innervation in gastrointestinal (GI) function...
November 2016: Journal of Alzheimer's Disease and Parkinsonism
https://www.readbyqxmd.com/read/28088342/nanoparticle-standards-for-immuno-based-quantitation-of-%C3%AE-synuclein-oligomers-in-diagnostics-of-parkinson-s-disease-and-other-synucleopathies
#4
Yvonne Herrmann, Tuyen Bujnicki, Christian Zafiu, Andreas Kulawik, Katja Kühbach, Luriano Peters, Judith Fabig, Johannes Willbold, Oliver Bannach, Dieter Willbold
Parkinson's disease is a neurodegenerative disorder that is characterized by symptoms such as rigor, tremor and bradykinesia. A reliable and early diagnosis could improve the development of early therapeutic strategies before death of dopaminergic neurons leads to the first clinical symptoms. The sFIDA (surface-based fluorescence intensity distribution analysis) assay is a highly sensitive method to determine the concentration of α-synuclein (α-syn) oligomers, which are presumably the major toxic isoform of α-syn and potentially the most direct biomarker for PD...
January 11, 2017: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/28086964/anti-%C3%AE-synuclein-immunotherapy-reduces-%C3%AE-synuclein-propagation-in-the-axon-and-degeneration-in-a-combined-viral-vector-and-transgenic-model-of-synucleinopathy
#5
Brian Spencer, Elvira Valera, Edward Rockenstein, Cassia Overk, Michael Mante, Anthony Adame, Wagner Zago, Peter Seubert, Robin Barbour, Dale Schenk, Dora Games, Robert A Rissman, Eliezer Masliah
Neurodegenerative disorders such as Parkinson's Disease (PD), PD dementia (PDD) and Dementia with Lewy bodies (DLB) are characterized by progressive accumulation of α-synuclein (α-syn) in neurons. Recent studies have proposed that neuron-to-neuron propagation of α-syn plays a role in the pathogenesis of these disorders. We have previously shown that antibodies against the C-terminus of α-syn reduce the intra-neuronal accumulation of α-syn and related deficits in transgenic models of synucleinopathy, probably by abrogating the axonal transport and accumulation of α-syn in in vivo models...
January 13, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28078567/the-c-abl-inhibitor-in-parkinson-disease
#6
REVIEW
Zhi-Hua Zhou, Yun-Fan Wu, Xue-Min Wang, Yong-Zhu Han
Parkinson's disease (PD) is an insidious onset neurodegenerative disease affecting approximately 1% of the population over the age of 65. So far available therapies for PD have only aimed at improving or alleviating symptoms, but not at slowing, preventing, and reversing the course of PD. Recently, some studies have indicated that the levels and activation of Abelson non-receptor tyrosine kinase (c-Abl, Abl1) were up-regulated in the brain tissue of patients with PD and demonstrated that c-Abl inhibitors could improve motor behavior, prevent the loss of dopamine neurons, inhibit phosphorylation of Cdk5, regulate α-synuclein phosphorylation and clearance, inhibit the tyrosine phosphorylation of parkin and decrease parkin substrate, for example, PARIS (zinc finger protein 746), AIMP2 (aminoacyl-tRNA synthetase-interacting multifunctional protein type2), FBP1 (fuse-binding protein 1), and synphilin-1...
January 11, 2017: Neurological Sciences
https://www.readbyqxmd.com/read/28078311/common-variant-rs356182-near-snca-defines-a-parkinson-s-disease-endophenotype
#7
Christine A Cooper, Nimansha Jain, Michael D Gallagher, Daniel Weintraub, Sharon X Xie, Yosef Berlyand, Alberto J Espay, Joseph Quinn, Karen L Edwards, Thomas Montine, Vivianna M Van Deerlin, John Trojanowski, Cyrus P Zabetian, Alice S Chen-Plotkin
OBJECTIVE: Parkinson's disease (PD) presents clinically with several motor subtypes that exhibit variable treatment response and prognosis. Here, we investigated genetic variants for their potential association with PD motor phenotype and progression. METHODS: We screened 10 SNPs, previously associated with PD risk, for association with tremor-dominant (TD) versus postural-instability gait disorder (PIGD) motor subtypes. SNPs that correlated with the TD/PIGD ratio in a discovery cohort of 251 PD patients were then evaluated in a multi-site replication cohort of 559 PD patients...
January 2017: Annals of Clinical and Translational Neurology
https://www.readbyqxmd.com/read/28075555/familial-mutations-may-switch-conformational-preferences-in-%C3%AE-synuclein-fibrils
#8
Liang Xu, Buyong Ma, Ruth Nussinov, Damien Thompson
The pathogenesis of Parkinson's disease is closely associated with the aggregation of the α-synuclein protein. Several familial mutants have been identified and shown to affect the aggregation kinetics of α-synuclein through distinct molecular mechanisms. Quantitative evaluation of the relative stabilities of the wild type and mutant fibrils is crucial for understanding the aggregation process and identifying the key component steps. In this work, we examined two topologically different α-synuclein fibril structures that are either determined by solid-state NMR method or modelled based on solid-state NMR data, and characterized their conformational properties and thermodynamic stabilities using molecular dynamics simulations...
January 11, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28069931/the-search-for-a-peripheral-biopsy-indicator-of-%C3%AE-synuclein-pathology-for-parkinson-disease
#9
REVIEW
John M Lee, Pascal Derkinderen, Jeffrey H Kordower, Roy Freeman, David G Munoz, Thomas Kremer, Wagner Zago, Samantha J Hutten, Charles H Adler, Geidy E Serrano, Thomas G Beach
The neuropathological hallmark of Parkinson disease (PD) is abnormal accumulation of α-synuclein (α-syn). Demonstrating pathological α-syn in live patients would be useful for identifying and monitoring PD patients. To date, however, imaging and biofluid approaches have not permitted premortem assessment of pathological α-syn. α-syn pathology in the peripheral nervous system of patients with PD has been demonstrated in studies dating back more than 40 years. More recent work suggests that colon, submandibular gland and skin biopsies could be useful as expedient biomarkers but histological differentiation of pathological and normal peripheral α-syn has been challenging and multiple research groups have reported variable results...
January 9, 2017: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/28069058/endosulfine-alpha-inhibits-membrane-induced-%C3%AE-synuclein-aggregation-and-protects-against-%C3%AE-synuclein-neurotoxicity
#10
Daniel Ysselstein, Benjamin Dehay, Isabel M Costantino, George P McCabe, Matthew P Frosch, Julia M George, Erwan Bezard, Jean-Christophe Rochet
Neuropathological and genetic findings suggest that the presynaptic protein α-synuclein (aSyn) is involved in the pathogenesis of synucleinopathy disorders, including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy. Evidence suggests that the self-assembly of aSyn conformers bound to phospholipid membranes in an aggregation-prone state plays a key role in aSyn neurotoxicity. Accordingly, we hypothesized that protein binding partners of lipid-associated aSyn could inhibit the formation of toxic aSyn oligomers at membrane surfaces...
January 10, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28068606/trehalose-does-not-improve-neuronal-survival-on-exposure-to-alpha-synuclein-pre-formed-fibrils
#11
Matthew Redmann, Willayat Y Wani, Laura Volpicelli-Daley, Victor Darley-Usmar, Jianhua Zhang
Parkinson's disease is a debilitating neurodegenerative disorder that is pathologically characterized by intracellular inclusions comprised primarily of alpha-synuclein (αSyn) that can also be transmitted from neuron to neuron. Several lines of evidence suggest that these inclusions cause neurodegeneration. Thus exploring strategies to improve neuronal survival in neurons with αSyn aggregates is critical. Previously, exposure to αSyn pre-formed fibrils (PFFs) has been shown to induce aggregation of endogenous αSyn resulting in cell death that is exacerbated by either starvation or inhibition of mTOR by rapamycin, both of which are able to induce autophagy, an intracellular protein degradation pathway...
January 3, 2017: Redox Biology
https://www.readbyqxmd.com/read/28062370/treadmill-exercise-alleviates-motor-deficits-and-improves-mitochondrial-import-machinery-in-an-mptp-induced-mouse-model-of-parkinson-s-disease
#12
Jung-Hoon Koo, Joon-Yong Cho, Ung-Bae Lee
Alpha-synuclein (α-Syn) accumulation is significantly correlated with motor deficits and mitochondrial dysfunction in Parkinson's disease (PD), but the molecular mechanism underlying its pathogenesis is unclear. In this study, we investigated the effects of treadmill exercise on motor deficits and mitochondrial dysfunction in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Treadmill exercise inhibited dopaminergic neuron loss by promoting the expression of tyrosine hydroxylase (TH) and dopamine transporter (DAT) and seemed to improve cell survival by reducing α-Syn expression...
January 3, 2017: Experimental Gerontology
https://www.readbyqxmd.com/read/28057070/distinct-pattern-of-enteric-phospho-alpha-synuclein-aggregates-and-gene-expression-profiles-in-patients-with-parkinson-s-disease
#13
Martina Barrenschee, Dimitri Zorenkov, Martina Böttner, Christina Lange, François Cossais, Amelie Bernadette Scharf, Günther Deuschl, Susanne A Schneider, Mark Ellrichmann, Annette Fritscher-Ravens, Thilo Wedel
Phosphorylated alpha-synuclein (p-α-syn) containing Lewy bodies (LBs) and Lewy neurites (LNs) are neuropathological hallmarks of Parkinson's disease (PD) in the central nervous system (CNS). Since they have been also demonstrated in the enteric nervous system (ENS) of PD patients, the aim of the study was to analyze enteric p-α-syn positive aggregates and intestinal gene expression. Submucosal rectal biopsies were obtained from patients with PD and controls and processed for dual-label-immunohistochemistry for p-α-syn and PGP 9...
January 5, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28056734/metal-nanoparticles-for-the-treatment-and-diagnosis-of-neurodegenerative-brain-diseases
#14
Valentina Vio, María José Marchant, Eyleen Araya, Marcelo J Kogan
This review focuses on the application of metal nanoparticles in the diagnosis and treatment of Alzheimer's and Parkinson's diseases. Metal nanoparticles present interesting physicochemical properties that can be applied to increase biomarker detection sensitivities in vitro and in vivo. Furthermore, these nanoparticles could be used in different strategies for the treatment of central nervous system diseases, particularly in regards to drug delivery. Herein, specific potential applications of metal nanoparticles are separately discussed for the contexts of in vitro diagnoses and treatments...
January 5, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28053029/mutant-%C3%AE-synuclein-overexpression-induces-stressless-pacemaking-in-vagal-motoneurons-at-risk-in-parkinson-s-disease
#15
Efrat Lasser-Katz, Alon Simchovitz, Wei-Hua Chiu, Wolfgang H Oertel, Ronit Sharon, Hermona Soreq, Jochen Roeper, Joshua A Goldberg
: α-Synuclein overexpression (ASOX) drives the formation of toxic aggregates in neurons vulnerable in Parkinson's disease (PD), including dopaminergic neurons of the substantia nigra (SN) and cholinergic neurons of the dorsal motor nucleus of the vagus (DMV). Just as these populations differ in when they exhibit α-synucleinopathies during PD pathogenesis, they could also differ in their physiological responses to ASOX. An ASOX-mediated hyperactivity of SN dopamine neurons, which was caused by oxidative dysfunction of Kv4...
January 4, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28052246/synucleins-have-multiple-effects-on-presynaptic-architecture
#16
Karina J Vargas, Nikolas Schrod, Taylor Davis, Ruben Fernandez-Busnadiego, Yumiko V Taguchi, Ulrike Laugks, Vladan Lucic, Sreeganga S Chandra
Synucleins (α, β, γ-synuclein) are a family of abundant presynaptic proteins. α-Synuclein is causally linked to the pathogenesis of Parkinson's disease (PD). In an effort to define their physiological and pathological function or functions, we investigated the effects of deleting synucleins and overexpressing α-synuclein PD mutations, in mice, on synapse architecture using electron microscopy (EM) and cryoelectron tomography (cryo-ET). We show that synucleins are regulators of presynapse size and synaptic vesicle (SV) pool organization...
January 3, 2017: Cell Reports
https://www.readbyqxmd.com/read/28050792/alpha-synuclein-alters-differently-gene-expression-of-sirts-parps-and-other-stress-response-proteins-implications-for-neurodegenerative-disorders
#17
J Motyl, P L Wencel, M Cieślik, R P Strosznajder, J B Strosznajder
Alpha-synuclein (ASN) is a presynaptic protein that can easily change its conformation under different types of stress. It's assumed that ASN plays an important role in the pathogenesis of Parkinson's and Alzheimer's disease. However, the molecular mechanism of ASN toxicity has not been elucidated. This study focused on the role of extracellular ASN (eASN) in regulation of transcription of sirtuins (Sirts) and DNA-bound poly(ADP-ribose) polymerases (PARPs) - proteins crucial for cells' survival/death. Our results indicate that eASN enhanced the free radicals level, decreased mitochondria membrane potential, cells viability and activated cells' death...
January 3, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28049716/sideroflexin-3-is-a-%C3%AE-synuclein-dependent-mitochondrial-protein-that-regulates-synaptic-morphology
#18
Inês S Amorim, Laura C Graham, Roderick N Carter, Nicholas M Morton, Fella Hammachi, Tilo Kunath, Giuseppa Pennetta, Sarah M Carpanini, Jean C Manson, Douglas J Lamont, Thomas M Wishart, Thomas H Gillingwater
α-synuclein plays a central role in Parkinson's disease, where it contributes to the vulnerability of synapses to degeneration. However, the downstream mechanisms through which α-synuclein controls synaptic stability and degeneration are not fully understood. Here, comparative proteomics on synapses isolated from α-synuclein(-/-) mouse brain identified mitochondrial proteins as primary targets of α-synuclein, revealing 37 mitochondrial proteins not previously linked to α-synuclein or neurodegeneration pathways...
January 3, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28045494/site-specific-fluorescence-polarization-for-studying-the-disaggregation-of-%C3%AE-synuclein-fibrils-by-small-molecules
#19
Conor M Haney, Christina L Cleveland, Rebecca F Wissner, Lily Owei, Jaclyn Robustelli, Malcolm J Daniels, Merve Canyurt, Priscilla Rodriguez, Harry Ischiropoulos, Tobias Baumgart, E James Petersson
Fibrillar aggregates of the protein α-synuclein (αS) are one of the hallmarks of Parkinson's disease. Here, we show that measuring the fluorescence polarization (FP) of labels at several sites on αS allows one to monitor changes in the local dynamics of the protein after binding to micelles or vesicles, and during fibril formation. Most significantly, these site-specific FP measurements provide insight into structural remodeling of αS fibrils by small molecules and have the potential for use in moderate-throughput screens to identify small molecules that could be used to treat Parkinson's disease...
November 11, 2016: Biochemistry
https://www.readbyqxmd.com/read/28042771/oxidative-stress-pro-inflammatory-cytokines-and-antioxidants-regulate-expression-levels-of-micrornas-in-parkinson-s-disease
#20
Kedar N Prasad
Parkinson's disease (PD) is a slow progressive neurodegenerative disease associated with abnormal function of extrapyramidal system. Although several biochemical and genetic defects have been identified, increased oxidative stress and chronic inflammation are one of the earliest events that initiate and promote PD. Oxidative stress also participates in impaired non-motor symptoms.The levels of microRNAs that are evolutionarily conserved single-stranded non-coding RNAs of approximately 22 nucleotide in length are altered in PD...
January 2, 2017: Current Aging Science
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