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Alpha-synuclein

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https://www.readbyqxmd.com/read/29021741/the-neuroprotective-role-of-protein-quality-control-in-halting-the-development-of-alpha-synuclein-pathology
#1
REVIEW
Destiny-Love Manecka, Benoît Vanderperre, Edward A Fon, Thomas M Durcan
Synucleinopathies are a family of neurodegenerative disorders that comprises Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Each of these disorders is characterized by devastating motor, cognitive, and autonomic consequences. Current treatments for synucleinopathies are not curative and are limited to improvement of quality of life for affected individuals. Although the underlying causes of these diseases are unknown, a shared pathological hallmark is the presence of proteinaceous inclusions containing the α-synuclein (α-syn) protein in brain tissue...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/29017011/altered-volatile-organic-compounds-profile-in-transgenic-rats-bearing-a53t-mutation-of-human-alpha-synuclein-comparison-with-dopaminergic-and-serotonergic-denervation
#2
John P M Finberg, Yuval Aluf, Yelena Loboda, Morad K Nakhleh, Raneen Jeries, Manal Aboud, Salman Zubedat, Avi Avital, Soliman Khatib, Jacob Vaya, Hossam Haick
Early diagnosis of Parkinson's disease (PD) is of great importance due its progressive phenotype. Neuroprotective drugs could potentially slow down disease progression if used at early stages. Previously, we have reported an altered content of volatile organic compounds (VOCs) in the breath of rats following a 50% reduction in striatal dopamine (DA) content induced by 6-hydroxydopamine. We now report on the difference in the breath-print and content of VOCs between rats with mild and severe lesions of DA neurons, serotonergic neuronal lesions, and transgenic (Tg) rats carrying the PD-producing A53T mutation of the SNCA (alpha-synuclein) gene...
October 10, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28991700/cardiac-sympathetic-denervation-and-dementia-in-de-novo-parkinson-s-disease-a-7-year-follow-up-study
#3
Mun Hee Choi, Jung Han Yoon, Suk Woo Yong
BACKGROUND: Postganglionic cardiac sympathetic denervation is evident in patients with early-stage Parkinson's disease (PD). Cardiac iodine-123-meta-iodobenzylguanidine (MIBG) uptake is correlated with the non-motor symptoms of PD, suggesting that low cardiac MIBG uptake may reflect wider alpha-synuclein pathology. In addition, low cardiac MIBG could be related to orthostatic hypotension in PD, which may affect cognition. However, the prognostic validity of baseline MIBG scintigraphy in terms of the risk of subsequent dementia remains unclear...
October 15, 2017: Journal of the Neurological Sciences
https://www.readbyqxmd.com/read/28987463/therapeutic-approaches-to-target-alpha-synuclein-pathology
#4
REVIEW
Patrik Brundin, Kuldip D Dave, Jeffrey H Kordower
Starting two decades ago with the discoveries of genetic links between alpha-synuclein and Parkinson's disease risk and the identification of aggregated alpha-synuclein as the main protein constituent of Lewy pathology, alpha-synuclein has emerged as the major therapeutic target in Parkinson's disease and related synucleinopathies. Following the suggestion that alpha-synuclein pathology gradually spreads through the nervous system following a stereotypic pattern and the discovery that aggregated forms of alpha-synuclein can propagate pathology from one cell to another, and thereby probably aggravate existing deficits as well as generate additional symptoms, the idea that alpha-synuclein is a viable therapeutic target gained further support...
October 4, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28986235/alpha-synuclein-epigenetics-mitochondria-metabolism-calcium-traffic-circadian-dysfunction-in-parkinson-s-disease-an-integrated-strategy-for-management
#5
REVIEW
Oliver T Phillipson
The motor deficits which characterise the sporadic form of Parkinson's disease arise from age-related loss of a subset of dopamine neurons in the substantia nigra. Although motor symptoms respond to dopamine replacement therapies, the underlying disease process remains. This review details some features of the progressive molecular pathology and proposes deployment of a combination of nutrients: R-lipoic acid, acetyl-L-carnitine, ubiquinol, melatonin (or receptor agonists) and vitamin D3, with the collective potential to slow progression of these features...
October 3, 2017: Ageing Research Reviews
https://www.readbyqxmd.com/read/28986122/mitochondrial-ros-mediated-post-transcriptional-regulation-of-%C3%AE-synuclein-through-mir-7-and-mir-153
#6
Goun Je, Yoon-Seong Kim
Dysregulation of human alpha-synuclein (α-SYN) is one of the major contributors in the pathogenesis of Parkinson's disease. 1-methyl-4-phenylpyridinium (MPP(+)) is well known neurotoxin which increases α-SYN expression and causes dopaminergic neuronal death. Increasing evidence suggests microRNAs (miRNAs), especially miRNA-7 and miR-153, have important role in the regulation of α-SYN translation and they can prevent MPP(+)-mediated neuronal death. Here, we examined whether MPP(+)-mediated upregulation of α-SYN expression is directly related to miRNA-7 and miR-153...
October 3, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28985507/randomized-crispr-cas-transcriptional-perturbation-screening-reveals-protective-genes-against-alpha-synuclein-toxicity
#7
Ying-Chou Chen, Fahim Farzadfard, Nava Gharaei, William C W Chen, Jicong Cao, Timothy K Lu
The genome-wide perturbation of transcriptional networks with CRISPR-Cas technology has primarily involved systematic and targeted gene modulation. Here, we developed PRISM (Perturbing Regulatory Interactions by Synthetic Modulators), a screening platform that uses randomized CRISPR-Cas transcription factors (crisprTFs) to globally perturb transcriptional networks. By applying PRISM to a yeast model of Parkinson's disease (PD), we identified guide RNAs (gRNAs) that modulate transcriptional networks and protect cells from alpha-synuclein (αSyn) toxicity...
October 5, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28981227/-treatment-of-parkinson-s-disease
#8
S Dethy
Parkinson's disease in a neurodegenerative disorder that affects as many as 1-2 % of persons aged 60 years and older. Parkinson's disease occurs infrequently under 40 years of age, with major genetic implication. Alpha-synuclein plays significant pathogenic role in Parkinson's disease. Therapeutic advances based on a synucleinrelated mechanism are now developed : immunotherapy against alpha-synuclein for example. The diagnosis of Parkinson's disease remains mostly clinical. DatScan® may be helpful to distinguish parkinsonian syndrome and essential tremor...
2017: Revue Médicale de Bruxelles
https://www.readbyqxmd.com/read/28981090/is-trehalose-an-autophagic-inducer-unraveling-the-roles-of-non-reducing-disaccharides-on-autophagic-flux-and-alpha-synuclein-aggregation
#9
Ye-Seul Yoon, Eun-Duk Cho, Woo Jung Ahn, Kyung Won Lee, Seung-Jae Lee, He-Jin Lee
Autophagy is a pivotal intracellular process by which cellular macromolecules are degraded upon various stimuli. A failure in the degradation of autophagic substrates such as impaired organelles and protein aggregates leads to their accumulations, which are characteristics of many neurodegenerative diseases. Pharmacological activation of autophagy has thus been considered a prospective therapeutic approach for treating neurodegenerative diseases. Among a number of autophagy-inducing agents, trehalose has received attention for its beneficial effects in different disease models of neurodegeneration...
October 5, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28973645/alpha-synuclein-induces-the-unfolded-protein-response-in-parkinson-s-disease-snca-triplication-ipsc-derived-neurons
#10
Sabrina M Heman-Ackah, Raquel Manzano, Jeroen J M Hoozemans, Wiep Scheper, Rowan Flynn, Wilfried Haerty, Sally A Cowley, Andrew R Bassett, Matthew J A Wood
The recent generation of induced pluripotent stem cells (iPSCs) from a patient with Parkinson's disease (PD) resulting from triplication of the α-synuclein (SNCA) gene locus allows unprecedented opportunities to explore its contribution to the molecular pathogenesis of PD. We used the double-nicking CRISPR/Cas9 system to conduct site-specific mutagenesis of SNCA in these cells, generating an isogenic iPSC line with normalized SNCA gene dosage. Comparative gene expression analysis of neuronal derivatives from these iPSCs revealed an ER stress phenotype, marked by induction of the IRE1α/XBP1 axis of the unfolded protein response (UPR) and culminating in terminal UPR activation...
September 1, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28973502/proteome-profile-of-different-rat-brain-regions-after-sarin-intoxication
#11
Kalyani Chaubey, Syed Imteyaz Alam, D P Nagar, Chandra Kant Waghmare, S C Pant, Lokendra Singh, Nalini Srivastava, Bijoy K Bhattacharya
Sarin is an organophosphorus chemical warfare agent which irreversibly inhibits acetylcholinesterase. Acute toxicity after sarin exposure is due to hyper activation of the nicotinic and muscarinic receptor. Survivors of sarin exposure often develop long term neuropathology referred as organophosphorus ester induced chronic neurotoxicity. However, the exact mechanism of chronic neuro-toxicity is yet unknown. We studied proteomic changes in rat brain regions after 0.5 LD50 dose of sarin and investigated some milestone changes associated with long term CNS injury...
August 16, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28969384/the-l444p-gba1-mutation-enhances-alpha-synuclein-induced-loss-of-nigral-dopaminergic-neurons-in-mice
#12
Anna Migdalska-Richards, Michal Wegrzynowicz, Raffaella Rusconi, Giulio Deangeli, Donato A Di Monte, Maria G Spillantini, Anthony H V Schapira
Mutations in glucocerebrosidase 1 (GBA1) represent the most prevalent risk factor for Parkinson's disease. The molecular mechanisms underlying the link between GBA1 mutations and Parkinson's disease are incompletely understood. We analysed two aged (24-month-old) Gba1 mouse models, one carrying a knock-out mutation and the other a L444P knock-in mutation. A significant reduction of glucocerebrosidase activity was associated with increased total alpha-synuclein accumulation in both these models. Gba1 mutations alone did not alter the number of nigral dopaminergic neurons nor striatal dopamine levels...
October 1, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28968082/c-terminal-truncated-%C3%AE-synuclein-fibrils-contain-strongly-twisted-%C3%AE-sheets
#13
Aditya Iyer, Steven Joop Roeters, Vladimir Kogan, Sander Woutersen, Mireille M A E Claessens, Vinod Subramaniam
C-terminal truncations of monomeric wild-type alpha synuclein (henceforth WT-αS) have been shown to enhance the formation of amyloid aggregates both in vivo and in vitro and have been associated with accelerated progression of Parkinson's disease. The correlation with PD may not solely be influenced by faster aggregation, but also from the effect the deletion of C-terminal residues has on which fibril polymorphs are preferentially formed. Considering that different polymorphs are known to result in distinct pathologies, it is important to understand how these truncations affect the organization of αS into fibrils...
October 2, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28966932/frequency-of-gba-variants-in-autopsy-proven-multiple-system-atrophy
#14
Miriam Sklerov, Un Jung Kang, Christopher Liong, Lorraine Clark, Karen Marder, Michael Pauciulo, William C Nichols, Wendy K Chung, Lawrence S Honig, Etty Cortes, Jean Paul Vonsattel, Roy N Alcalay
BACKGROUND: Multiple system atrophy (MSA) is marked by abnormal inclusions of alpha-synuclein in oligodendrogliocytes. Etiology remains unknown. Variants in the glucocerebrosidase gene have been associated with other synucleinopathies, dementia with Lewy bodies and Parkinson disease. It is unclear whether glucocerebrosidase variants are associated with MSA. OBJECTIVES: To analyze the frequency of glucocerebrosidase gene variants among autopsy-proven cases of MSA at a brain bank in New York City...
July 2017: Movement Disorders Clinical Practice
https://www.readbyqxmd.com/read/28957336/a-study-on-the-modulation-of-alpha-synuclein-fibrillation-by-scutellaria-pinnatifida-extracts-and-its-neuroprotective-properties
#15
Mahdyeh Sashourpour, Saber Zahri, Tayebeh Radjabian, Viktoria Ruf, Francisco Pan-Montojo, Dina Morshedi
Aggregation of alpha-synuclein (α-SN) is a key pathogenic event in Parkinson's disease (PD) leading to dopaminergic degeneration. The identification of natural compounds inhibiting α-SN aggregation may have a major role in treating PD. Different Scutellaria species are known as valuable medicinal plants, primarily due to their high flavonoid levels. Scutellaria pinnatifida (S. pinnatifida) is endemic to Iran; however, the knowledge of its pharmaceutical properties is limited. Here we report that S. pinnatifida extracts have an anti-fibrillation effect on α-SN aggregation and neuroprotective properties on PC12 and primary dopaminergic neurons...
2017: PloS One
https://www.readbyqxmd.com/read/28955066/absence-of-snca-polymorphisms-in-pakistani-parkinsons-disease-patients
#16
Aneesa Sultan, Muhammad Asad Usmani, Maliha Ghaffar, Johar Ali, Mazhar Badshah, Nafees Ahmad
OBJECTIVE: To elucidate the genetic risk and role of alpha-synuclein gene in the pathogenesis of Parkinson's disease in Pakistani population. METHODS: This case-control study was conducted at Institute of Biomedical and Genetic Engineering (IBGE), Islamabad from May 2013 to May 2016, and comprised patients with Parkinson's disease and their ethnically-matched healthy controls. Allele-specific polymerase chain reaction was used for screening of three pathogenic single nucleotide polymorphisms in alpha-synuclein gene...
October 2017: JPMA. the Journal of the Pakistan Medical Association
https://www.readbyqxmd.com/read/28951838/alteration-in-biochemical-parameters-in-the-brain-of-transgenic-drosophila-melanogaster-model-of-parkinson-s-disease-exposed-to-apigenin
#17
Yasir Hasan Siddique, Smita Jyoti
BACKGROUND: Oxidative stress is one of the key components of the pathology of various neurodegenerative disorders. Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons owing to the aggregation of alpha-synuclein (αS) in the brain. A number of polyphenols have been reported to inhibit the αS aggregation resulting in the possible prevention of PD. The involvement of free radicals in mediating the neuronal death in PD has also been implicated. METHODS: In the present study, the transgenic flies expressing human αS in the brain were exposed to 10 μM, 20 μM, 40 μM, and 80 μM of apigenin established in diet for 24 days...
September 2017: Integrative medicine research
https://www.readbyqxmd.com/read/28951252/sex-dependent-alterations-in-motor-and-anxiety-like-behavior-of-aged-bacterial-peptidoglycan-sensing-molecule-2-knockout-mice
#18
Tim Arentsen, Roksana Khalid, Yu Qian, Rochellys Diaz Heijtz
Peptidoglycan recognition proteins (PGRPs) are key sensing-molecules of the innate immune system that specifically detect bacterial peptidoglycan (PGN) and its derivates. PGRPs have recently emerged as potential key regulators of normal brain development and behavior. To test the hypothesis that PGRPs play a role in motor control and anxiety-like behavior in later life, we used 15-month old male and female peptidoglycan recognition protein 2 (Pglyrp2) knockout (KO) mice. Pglyrp2 is an N-acetylmuramyl-L-alanine amidase that hydrolyzes PGN between the sugar backbone and the peptide chain (which is unique among the mammalian PGRPs)...
September 23, 2017: Brain, Behavior, and Immunity
https://www.readbyqxmd.com/read/28948653/molecular-mechanisms-of-the-co-deposition-of-multiple-pathological-proteins-in-neurodegenerative-diseases
#19
Takashi Nonaka, Masami Masuda-Suzukake, Masato Hasegawa
Intracellular inclusions composed of abnormal protein aggregates are one of the neuropathological features of neurodegenerative diseases, and the formation of intracellular aggregates is believed to be associated with neurodegeneration leading to the onset of these diseases. In typical or pure cases, characteristic pathologies with one particular protein, such as tau, alpha-synuclein or trans-activation response DNA protein 43 (TDP-43), can be observed in brains of patients. On the other hand, multiple protein pathologies co-exist in many cases, raising the possibility that they may influence each other reciprocally in the pathogenesis and progression of the diseases...
September 25, 2017: Neuropathology: Official Journal of the Japanese Society of Neuropathology
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
#20
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...
October 4, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
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