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https://www.readbyqxmd.com/read/28108534/cell-biology-and-pathophysiology-of-%C3%AE-synuclein
#1
Jacqueline Burré, Manu Sharma, Thomas C Südhof
α-Synuclein is an abundant neuronal protein that is highly enriched in presynaptic nerve terminals. Genetics and neuropathology studies link α-synuclein to Parkinson's disease (PD) and other neurodegenerative disorders. Accumulation of misfolded oligomers and larger aggregates of α-synuclein defines multiple neurodegenerative diseases called synucleinopathies, but the mechanisms by which α-synuclein acts in neurodegeneration are unknown. Moreover, the normal cellular function of α-synuclein remains debated...
January 20, 2017: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/28108532/tdp-43-prions
#2
Takashi Nonaka, Masato Hasegawa
The most common neurodegenerative diseases, such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, are all protein-misfolding diseases and are characterized by the presence of disease-specific protein aggregates in affected neuronal cells. Recent studies have shown that, like tau and α-synuclein, TAR-DNA binding protein of 43 kDa (TDP-43) can form aggregates in vitro in a seed-dependent, self-templating, prion-like manner. Insoluble TDP-43 prepared from the brains of patients has been classified into several strains, which can be transferred from cell to cell in vitro, suggesting the involvement of mechanisms reminiscent of those by which prions spread through the nervous system...
January 20, 2017: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/28108469/blood-rna-biomarkers-in-prodromal-park4-and-rem-sleep-behavior-disorder-show-role-of-complexin-1-loss-for-risk-of-parkinson-s-disease
#3
Suna Lahut, Suzana Gispert, Özgür Ömür, Candan Depboylu, Kay Seidel, Jorge Antolio Domínguez-Bautista, Nadine Brehm, Hülya Tireli, Karl Hackmann, Caroline Pirkevi, Barbara Leube, Vincent Ries, Kerstin Reim, Nils Brose, Wilfred F den Dunnen, Madrid Johnson, Zsuzsanna Wolf, Marc Schindewolf, Wiebke Schrempf, Kathrin Reetz, Peter Young, David Vadasz, Achilleas S Frangakis, Evelin Schröck, Helmuth Steinmetz, Marina Jendrach, Udo Rüb, Ayşe Nazlı Başak, Wolfgang Oertel, Georg Auburger
Parkinson's disease (PD) is a frequent neurodegenerative process at old age. Accumulation and aggregation of the lipid-binding SNARE complex component alpha-synuclein (SNCA) underlies this vulnerability and defines stages of disease progression. Determinants of SNCA levels and mechanisms of SNCA neurotoxicity are intensely investigated. In view of physiological SNCA roles in blood to modulate vesicle release, we studied blood samples from a new large pedigree with SNCA gene duplication (PARK4 mutation), to identify effects of SNCA gain-of-function as potential disease biomarkers...
January 20, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28106571/the-identification-of-alpha-synuclein-as%C3%A2-the%C3%A2-first-parkinson-disease-gene
#4
Robert L Nussbaum
No abstract text is available yet for this article.
January 17, 2017: Journal of Parkinson's Disease
https://www.readbyqxmd.com/read/28105108/downregulation-of-microrna-497-is-associated-with-upregulation-of-synuclein-%C3%AE-in-patients-with-osteosarcoma
#5
Liang Wang, Hongwei Gao, Ningji Gong, Mingzhi Gong
The present study aimed to investigate the effects of microRNA (miRNA/miR)-497 expression levels on the expression levels of synuclein γ (SNCG) in serum samples, as well as osteosarcoma and lung-metastatic tissue samples, from patients with osteosarcoma. Between December 2010 and August 2013, fasting peripheral blood was collected from 36 patients with osteosarcoma for serum separation. In addition, osteosarcoma and lung metastatic tissues were resected from 15 osteosarcoma patients with lung metastasis by surgery...
December 2016: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28104909/selective-neuronal-vulnerability-in-parkinson-disease
#6
D James Surmeier, José A Obeso, Glenda M Halliday
Intracellular α-synuclein (α-syn)-rich protein aggregates called Lewy pathology (LP) and neuronal death are commonly found in the brains of patients with clinical Parkinson disease (cPD). It is widely believed that LP appears early in the disease and spreads in synaptically coupled brain networks, driving neuronal dysfunction and death. However, post-mortem analysis of human brains and connectome-mapping studies show that the pattern of LP in cPD is not consistent with this simple model, arguing that, if LP propagates in cPD, it must be gated by cell- or region-autonomous mechanisms...
January 20, 2017: Nature Reviews. Neuroscience
https://www.readbyqxmd.com/read/28102321/the-chaperonin-cct-inhibits-assembly-of-%C3%AE-synuclein-amyloid-fibrils-by-a-specific-conformation-dependent-interaction
#7
Begoña Sot, Alejandra Rubio-Muñoz, Ahudrey Leal-Quintero, Javier Martínez-Sabando, Miguel Marcilla, Cintia Roodveldt, José M Valpuesta
The eukaryotic chaperonin CCT (chaperonin containing TCP-1) uses cavities built into its double-ring structure to encapsulate and to assist folding of a large subset of proteins. CCT can inhibit amyloid fibre assembly and toxicity of the polyQ extended mutant of huntingtin, the protein responsible for Huntington's disease. This raises the possibility that CCT modulates other amyloidopathies, a still-unaddressed question. We show here that CCT inhibits amyloid fibre assembly of α-synuclein A53T, one of the mutants responsible for Parkinson's disease...
January 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28096359/%C3%AE-synuclein-binds-and-sequesters-pike-l-into-lewy-bodies-triggering-dopaminergic-cell-death-via-ampk-hyperactivation
#8
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
#9
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/28092083/role-of-dopamine-d2-d3-receptors-in-development-plasticity-and-neuroprotection-in-human-ipsc-derived-midbrain-dopaminergic-neurons
#10
Federica Bono, Paola Savoia, Adele Guglielmi, Massimo Gennarelli, Giovanna Piovani, Sandra Sigala, Damiana Leo, Stefano Espinoza, Raul R Gainetdinov, Paola Devoto, PierFranco Spano, Cristina Missale, Chiara Fiorentini
The role of dopamine D2 and D3 receptors (D2R/D3R), located on midbrain dopaminergic (DA) neurons, in the regulation of DA synthesis and release and in DA neuron homeostasis has been extensively investigated in rodent animal models. By contrast, the properties of D2R/D3R in human DA neurons have not been elucidated yet. On this line, the use of human-induced pluripotent stem cells (hiPSCs) for producing any types of cells has offered the innovative opportunity for investigating the human neuronal phenotypes at the molecular levels...
January 14, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28090391/neurotoxin-induced-catecholaminergic-loss-in-the-colonic-myenteric-plexus-of-rhesus-monkeys
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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/28071698/increased-levels-of-csf-total-but-not-oligomeric-or-phosphorylated-forms-of-alpha-synuclein-in-patients-diagnosed-with-probable-alzheimer-s-disease
#17
Nour K Majbour, Davide Chiasserini, Nishant N Vaikath, Paolo Eusebi, Takahiko Tokuda, Wilma van de Berg, Lucilla Parnetti, Paolo Calabresi, Omar M A El-Agnaf
Several studies reported an association between CSF alpha-synuclein (α-syn) and tau in Alzheimer's disease (AD), and demonstrated the significance of α-syn in improving the diagnostic sensitivity/specificity of classical AD CSF biomarkers. In the current study, we measured CSF levels of different α-syn species in a cohort of AD patients (n = 225) who showed a CSF profile typical of AD at baseline as well as in cognitively intact controls (n = 68). CSF total α-syn (t-α-syn) significantly increased in the AD group (p < 0...
January 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28069931/the-search-for-a-peripheral-biopsy-indicator-of-%C3%AE-synuclein-pathology-for-parkinson-disease
#18
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
#19
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
#20
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
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