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alpha synuclein and aggregation

Elena Abati, Alessio Di Fonzo, Stefania Corti
Multiple system atrophy (MSA) is a rare neurodegenerative disease with a fatal outcome. Nowadays, only symptomatic treatment is available for MSA patients. The hallmarks of the disease are glial cytoplasmic inclusions (GCIs), proteinaceous aggregates mainly composed of alpha-synuclein, which accumulate in oligodendrocytes. However, despite the extensive research efforts, little is known about the pathogenesis of MSA. Early myelin dysfunction and alpha-synuclein deposition are thought to play a major role, but the origin of the aggregates and the causes of misfolding are obscure...
March 4, 2018: Journal of Cellular and Molecular Medicine
Alan J Fowler, Charbel E-H Moussa
Parkinson's disease is a progressive neurodegenerative disease characterized by Lewy body pathology of which the primary constituent is aggregated misfolded alpha-synuclein protein. Currently, there are no clinical therapies for treatment of the underlying alpha-synuclein dysfunction and accumulation, and the standard of care for patients with Parkinson's disease focuses only on symptom management, creating an immense therapeutic gap that needs to be filled. Defects in autophagy have been strongly implicated in Parkinson's disease...
February 28, 2018: CNS Drugs
Jennifer A Steiner, Emmanuel Quansah, Patrik Brundin
Parkinson's disease is characterized by the loss of nigrostriatal dopaminergic signaling and the presence of alpha-synuclein aggregates (also called Lewy bodies and neurites) throughout the brain. In 2003, Braak and colleagues created a staging system for Parkinson's disease describing the connection between the alpha-synuclein pathology and disease severity. Later, they suggested that the pathology might initially be triggered by exogenous insults targeting the gut and olfactory system. In 2008, we and other groups documented Lewy pathology in grafted neurons in people with Parkinson's disease who had been transplanted over a decade prior to autopsy...
February 26, 2018: Cell and Tissue Research
Dasiel O Borroto-Escuela, Sonja Hinz, Gemma Navarro, Rafael Franco, Christa E Müller, Kjell Fuxe
Adenosine is a nucleoside mainly formed by degradation of ATP, located intracellularly or extracellularly, and acts as a neuromodulator. It operates as a volume transmission signal through diffusion and flow in the extracellular space to modulate the activity of both glial cells and neurons. The effects of adenosine are mediated via four adenosine receptor subtypes: A1R, A2AR, A2BR, A3R. The A2AR has a wide-spread distribution but it is especially enriched in the ventral and dorsal striatum where it is mainly located in the striato-pallidal GABA neurons at a synaptic and extrasynaptic location...
2018: Frontiers in Neuroscience
John Forsayeth, Piotr Hadaczek
Here we advance the hypothesis that Parkinson's disease (PD) is fundamentally a failure of trophic support for specific classes of neurons, primarily catecholaminergic. Evidence from our laboratory provides a framework into which a broad array of findings from many quarters can be integrated into a general theory that offers testable hypotheses to new and established investigators. Mice deficient in the ability to synthesize series-a gangliosides, specifically GM1 ganglioside, develop parkinsonism. We found that this seems to be due to a failure in signaling efficiency by the important catecholaminergic growth factor, GDNF...
2018: Frontiers in Neuroscience
C E Shepherd, Y Yang, G M Halliday
Variations in genomic DNA content, or aneuploidy, are a well-recognized feature of normal human brain development. Whether changes in the levels of aneuploidy are a factor in Alzheimer's disease (AD) is less clear, as the data reported to date vary substantially in the levels of aneuploidy detected (0.7-11.5%), possibly due to methodological limitations, but also influenced by individual, regional and cellular heterogeneity as well as variations in cell subtypes. These issues have not been adequately addressed to date...
February 9, 2018: Neuroscience
Abeje Ambaw, Lingxing Zheng, Mitali A Tambe, Katherine E Strathearn, Glen Acosta, Scott A Hubers, Fang Liu, Seth A Herr, Jonathan Tang, Alan Truong, Elwood Walls, Amber Pond, Jean-Christophe Rochet, Riyi Shi
Growing evidence suggests that oxidative stress plays a critical role in neuronal destruction characteristic of Parkinson's disease (PD). However, the molecular mechanisms of oxidative stress-mediated dopaminergic cell death are far from clear. In the current investigation, we tested the hypothesis that acrolein, an oxidative stress and lipid peroxidation (LPO) product, is a key factor in the pathogenesis of PD. Using a combination of in vitro, in vivo, and cell free models, coupled with anatomical, functional, and behavioral examination, we found that acrolein was elevated in 6-OHDA-injected rats, and behavioral deficits associated with 6-OHDA could be mitigated by the application of the acrolein scavenger hydralazine, and mimicked by injection of acrolein in healthy rats...
January 29, 2018: Molecular and Cellular Neurosciences
Jimena Hebe Martinez, Agustina Alaimo, Roxana Mayra Gorojod, Soledad Porte Alcon, Federico Fuentes, Federico Coluccio Leskow, Mónica Lidia Kotler
Parkinson's disease is a neurodegenerative movement disorder caused by the loss of dopaminergic neurons from substantia nigra. It is characterized by the accumulation of aggregated α-synuclein as the major component of the Lewy bodies. Additional common features of this disease are the mitochondrial dysfunction and the activation/inhibition of autophagy both events associated to the intracellular accumulation of α-synuclein. The mechanism by which these events contribute to neural degeneration remains unknown...
January 27, 2018: Molecular and Cellular Neurosciences
Veselin Grozdanov, Karin M Danzer
Parkinson's disease (PD) is a chronic progressive neurodegenerative disease, which is characterized by severe loss of dopaminergic neurons and formation of Lewy bodies, which are rich in aggregated alpha-synuclein (α-syn). Two decades of intensive research have compiled a massive body of evidence that aggregation of α-syn is a critical process in PD and other synucleinopathies. The dissemination of Lewy body pathology throughout the central nervous system strongly suggests a cell-to-cell transmission of α-syn...
February 6, 2018: Cell and Tissue Research
Xiaoyu Shi, Yue Sun, Ping Wang, Lingling Gu, Lu Wang, Huan Yang, Qun Wei, Zhimei Li, Jing Luo
Calcineurin (CN) is a protein phosphatase and widely distributed in eukaryotes, with an extremely high level of expression in mammalian brain. Alpha-synuclein (α-syn) is a small soluble protein expressed primarily at presynaptic terminals in the central nervous system. In our present study, we explored the interactions between CN and α-syn in vitro. Based on the data from microscale thermophoresis, GST pull-down assays, and co-immunoprecipitation, we found that CN binds α-syn. Furthermore, this interaction is mediated by calcium/calmodulin (Ca2+/CaM) signaling...
January 30, 2018: Biochemical and Biophysical Research Communications
Kseniya Barinova, Evgeniya Khomyakova, Pavel Semenyuk, Elena Schmalhausen, Vladimir Muronetz
According to literature data, the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) co-localizes with alpha-synuclein in Lewy bodies in Parkinson's disease, which suggests the involvement of this protein in the development of synucleinopathies. The goal of the present work was to investigate the direct interaction between alpha-synuclein and GAPDH and to evaluate possible influence of this interaction on the catalytic properties of GAPDH. Molecular dynamic simulations predicted the binding of alpha-synuclein to the positively charged groove comprising NAD+-binding pocket of GAPDH...
February 3, 2018: Archives of Biochemistry and Biophysics
Roberta Balestrino, Anthony H V Schapira
Parkinson disease (PD) is a complex neurodegenerative disease characterised by multiple motor and non-motor symptoms. In the last 20 years, more than 20 genes have been identified as causes of parkinsonism. Following the observation of higher risk of PD in patients affected by Gaucher disease, a lysosomal disorder caused by mutations in the glucocerebrosidase (GBA) gene, it was discovered that mutations in this gene constitute the single largest risk factor for development of idiopathic PD. Patients with PD and GBA mutations are clinically indistinguishable from patients with idiopathic PD, although some characteristics emerge depending on the specific mutation, such as slightly earlier onset...
February 1, 2018: Neuroscientist: a Review Journal Bringing Neurobiology, Neurology and Psychiatry
Zsolt Datki, Zita Olah, Tibor Hortobagyi, Lilla Macsai, Katalin Zsuga, Livia Fulop, Zsolt Bozso, Bence Galik, Eva Acs, Angela Foldi, Amanda Szarvas, Janos Kalman
Neurodegenerative diseases are linked to a systemic enzyme resistance of toxic aggregated molecules and their pathological consequences. This paper presents a unique phenomenon that Philodina acuticornis, a bdelloid rotifer, is able to catabolize different types of neurotoxic peptide and protein aggregates (such as beta-amyloids /Aβ/, alpha-synuclein, and prion) without suffering any damage. P. acuticornis is capable of using these aggregates as an exclusive energy source (i.e., as 'food', identified in the digestive system and body) in a hermetically isolated microdrop environment, increasing their survival...
January 29, 2018: Acta Neuropathologica Communications
Ana Gámez-Valero, Katrin Beyer
The synuclein family is composed of three members, two of which, α- and β-synuclein, play a major role in the development of synucleinopathies, including Parkinson's disease (PD) as most important movement disorder, dementia with Lewy bodies (DLB) as the second most frequent cause of dementia after Alzheimer's disease and multiple system atrophy. Whereas abnormal oligomerization and fibrillation of α-synuclein are now well recognized as initial steps in the development of synucleinopathies, β-synuclein is thought to be a natural α-synuclein anti-aggregant...
January 25, 2018: Genes
Reinis Svarcbahs, Ulrika H Julku, Susanna Norrbacka, Timo T Myöhänen
Prolyl oligopeptidase (PREP) inhibition by small-molecule inhibitors can reduce alpha-synuclein (aSyn) aggregation, a key player in Parkinson's disease pathology. However, the significance of PREP protein for aSyn aggregation and toxicity is not known. We studied this in vivo by using PREP knock-out mice with viral vector injections of aSyn and PREP. Animal behavior was studied by locomotor activity and cylinder tests, microdialysis and HPLC were used to analyze dopamine levels, and different aSyn forms and loss of dopaminergic neurons were studied by immunostainings...
January 24, 2018: Scientific Reports
Aleksandr Kakinen, Ibrahim Javed, Ava Faridi, Thomas P Davis, Pu Chun Ke
Protein aggregation is a ubiquitous phenomenon underpinning the origins of a range of human diseases. The amyloid aggregation of human islet amyloid polypeptide (IAPP) and alpha synuclein (αS), specifically, is a hallmark of type 2 diabetes (T2D) and Parkinson's disease impacting millions of people worldwide. Although IAPP and αS are strongly associated with pancreatic β-cell islets and presynaptic terminals, they have also been found in blood circulation and the gut. While extensive biophysical and biochemical studies have been focused on IAPP and αS interacting with cell membranes or model lipid vesicles, the roles of plasma proteins on the amyloidosis and membrane association of these two major types of amyloid proteins have rarely been examined...
January 20, 2018: Biochimica et Biophysica Acta
Fredric P Manfredsson, Kelvin C Luk, Matthew J Benskey, Aysegul Guezer, Joanna Garcia, Nathan C Kuhn, Ivette M Sandoval, Joseph R Patterson, Alana O'Mara, Reid Yonkers, Jeffrey H Kordower
Alpha-Synuclein (α-syn) is by far the most highly vetted pathogenic and therapeutic target in Parkinson's disease. Aggregated α-syn is present in sporadic Parkinson's disease, both in the central nervous system (CNS) and peripheral nervous system (PNS). The enteric division of the PNS is of particular interest because 1) gastric dysfunction is a key clinical manifestation of Parkinson's disease, and 2) Lewy pathology in myenteric and submucosal neurons of the enteric nervous system (ENS) has been referred to as stage zero in the Braak pathological staging of Parkinson's disease...
January 13, 2018: Neurobiology of Disease
Mari Suzuki, Kazunori Sango, Keiji Wada, Yoshitaka Nagai
Alpha-synuclein (αSyn) plays a central role in the pathogenesis of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In sporadic PD and DLB, normally harmless αSyn proteins without any mutations might gain toxic functions by unknown mechanisms. Thus, it is important to elucidate the factors promoting the toxic conversion of αSyn, towards understanding the pathogenesis of and developing disease-modifying therapies for PD and DLB. Accumulating biophysical and biochemical studies have demonstrated that αSyn interacts with lipid membrane, and the interaction influences αSyn oligomerization and aggregation...
January 3, 2018: Neurochemistry International
Hideki Mochizuki, Chi-Jing Choong, Eliezer Masliah
α-synuclein (αSyn) still remains a mysterious protein even two decades after SNCA encoding it was identified as the first causative gene of familial Parkinson's disease (PD). Accumulation of αSyn causes α-synucleinopathies including PD, dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Recent advances in therapeutic approaches offer new antibody-, vaccine-, antisense-oligonucleotide- and small molecule-based options to reduce αSyn protein levels and aggregates in patient's brain. Gathering research information of other neurological disease particularly Alzheimer's disease, recent disappointment of an experimental amyloid plaques busting antibody in clinical trials underscores the difficulty of treating people who show even mild dementia as damage in their brain may already be too extensive...
January 2, 2018: Neurochemistry International
Tracey Evans, Wai Ling Kok, Katrina Cowan, Megan Hefford, Oleg Anichtchik
Dementia with Lewy bodies (DLB) is the second most prevalent neurodegenerative dementia, where an accumulation of aggregated fibrillar alpha-synuclein in neurons of limbic and forebrain regions of the brain leads to visual hallucination, cognitive impairment of a fluctuating nature and extrapyramidal motor disturbances. Beta-synuclein counteracts aggregation of alpha-synuclein in vitro and in animal models, however it is not clear whether this effect occurs in human Lewy body dementia (LBD) diseases. Here we examine expression of alpha-, beta-synuclein and autophagy markers in the frontal cortex (BA9) and occipital cortex (BA18-19) of patients with neuropathologically confirmed DLB/LBD and age-matched controls...
December 23, 2017: Brain Research
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