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Alpha-synuclein

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https://www.readbyqxmd.com/read/29236052/micrornas-in-parkinson-s-disease-from-pathogenesis-to-novel-diagnostic-and-therapeutic-approaches
#1
REVIEW
Loredana Leggio, Silvia Vivarelli, Francesca L'Episcopo, Cataldo Tirolo, Salvo Caniglia, Nunzio Testa, Bianca Marchetti, Nunzio Iraci
Parkinson's disease (PD) is the most prevalent central nervous system (CNS) movement disorder and the second most common neurodegenerative disease overall. PD is characterized by the progressive loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc) within the midbrain, accumulation of alpha-synuclein (α-SYN) in Lewy bodies and neurites and excessive neuroinflammation. The neurodegenerative processes typically begin decades before the appearance of clinical symptoms. Therefore, the diagnosis is achievable only when the majority of the relevant DAergic neurons have already died and for that reason available treatments are only palliative at best...
December 13, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29233723/the-different-faces-of-the-p-a53t-alpha-synuclein-mutation-a-screening-of-greek-patients-with-parkinsonism-and-or-dementia
#2
Marianthi Breza, Georgios Koutsis, Georgia Karadima, Constantin Potagas, Chrisoula Kartanou, Sokratis G Papageorgiou, George P Paraskevas, Elisabeth Kapaki, Leonidas Stefanis, Marios Panas
BACKGROUND: The p. A53T mutation in the alpha-synuclein (SNCA) gene is a rare cause of autosomal dominant Parkinson's disease (PD). Although generally rare, it is particularly common in the Greek population due to a founder effect. A53T-positive PD patients often develop dementia during disease course and may very rarely present with dementia. METHODS: We screened for the p. A53T SNCA mutation a total of 347 cases of Greek origin with parkinsonism and/or dementia, collected over 15 years at the Neurogenetics Unit, Eginition Hospital, University of Athens...
December 9, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/29228971/alpha-synuclein-oligomer-selective-antibodies-reduce-intracellular-accumulation-and-mitochondrial-impairment-in-alpha-synuclein-exposed-astrocytes
#3
Gabriel Gustafsson, Veronica Lindström, Jinar Rostami, Eva Nordström, Lars Lannfelt, Joakim Bergström, Martin Ingelsson, Anna Erlandsson
BACKGROUND: Due to its neurotoxic properties, oligomeric alpha-synuclein (α-syn) has been suggested as an attractive target for passive immunization against Parkinson's disease (PD). In mouse models of PD, antibody treatment has been shown to lower the levels of pathogenic α-syn species, including oligomers, although the mechanisms of action remain unknown. We have previously shown that astrocytes rapidly engulf α-syn oligomers that are intracellularly stored, rather than degraded, resulting in impaired mitochondria...
December 11, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/29227247/stress-induced-cdk5-activity-enhances-cytoprotective-basal-autophagy-in-drosophila-melanogaster-by-phosphorylating-acinus-at-serine437
#4
Nilay Nandi, Lauren K Tyra, Drew Stenesen, Helmut Krämer
Cdk5 is a post-mitotic kinase with complex roles in maintaining neuronal health. The various mechanisms by which Cdk5 inhibits and promotes neurodegeneration are still poorly understood. Here, we show that in Drosophila melanogaster Cdk5 regulates basal autophagy, a key mechanism suppressing neurodegeneration. In a targeted screen, Cdk5 genetically interacted with Acinus (Acn), a primarily nuclear protein, which promotes starvation-independent, basal autophagy. Loss of Cdk5, or its required cofactor p35, reduces S437-Acn phosphorylation, whereas Cdk5 gain-of-function increases pS437-Acn levels...
December 11, 2017: ELife
https://www.readbyqxmd.com/read/29225795/multiple-system-atrophy-genetic-risks-and-alpha-synuclein-mutations
#5
REVIEW
Heather T Whittaker, Yichen Qui, Conceição Bettencourt, Henry Houlden
Multiple system atrophy (MSA) is one of the few neurodegenerative disorders where we have a significant understanding of the clinical and pathological manifestations but where the aetiology remains almost completely unknown. Research to overcome this hurdle is gaining momentum through international research collaboration and a series of genetic and molecular discoveries in the last few years, which have advanced our knowledge of this rare synucleinopathy. In MSA, the discovery of α-synuclein pathology and glial cytoplasmic inclusions remain the most significant findings...
2017: F1000Research
https://www.readbyqxmd.com/read/29218419/an-unexpected-improvement-in-spatial-learning-and-memory-ability-in-alpha-synuclein-a53t-transgenic-mice
#6
Qi Liu, YuYu Xu, WenPing Wan, ZeGang Ma
Growing evidence suggests, as Parkinson's disease (PD) progresses, that its non-motor symptoms appear prior to or in parallel with its motor deficits. Alpha-synuclein A53T transgenic mouse (A53T) is an essential tool to investigate the onsets and the extents of PD non-motor symptoms. Our aim is to investigate spatial learning and memory ability in A53T mice. In our rotarod tests, no motor coordination impairments were detected in mice of 3, 6, 9, and 12 months old. We then investigated their spatial learning and memory ability through Morris water maze in 3- and 9-month-old mice...
December 7, 2017: Journal of Neural Transmission
https://www.readbyqxmd.com/read/29217686/synaptic-regulator-%C3%AE-synuclein-in-dopaminergic-fibers-is-essentially-required-for-the-maintenance-of-subependymal-neural-stem-cells
#7
Ana Perez-Villalba, Mª Salomé Sirerol-Piquer, Germán Belenguer, Raúl Soriano-Cantón, Ana Belén Muñoz-Manchado, Javier Villadiego, Diana Alarcón-Arís, Federico N Soria, Benjamin Dehay, Erwan Bezard, Miquel Vila, Analía Bortolozzi, Juan José Toledo-Aral, Francisco Pérez-Sánchez, Isabel Fariñas
Synaptic protein α-synuclein (α-SYN) modulates neurotransmission in a complex and poorly understood manner and aggregates in the cytoplasm of degenerating neurons in Parkinson's disease. Here, we report that α-SYN present in dopaminergic nigral afferents is essential for the normal cycling and maintenance of neural stem cells (NSCs) in the brain subependymal zone of adult male and female mice. We also show that premature senescence of adult NSCs into non-neurogenic astrocytes in mice lacking α-SYN resembles the effects of dopaminergic fiber degeneration resulting from chronic exposure to MPTP or intranigral inoculation of aggregated toxic α-SYN...
December 6, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29217261/synucleinopathies-in-neurodegenerative-diseases-accomplices-an-inside-job-and-selective-vulnerability
#8
S Ausim Azizi, Saara-Anne Azizi
Pathogenesis of degenerative diseases is complex and multifaceted. The disease phenotypes depend on the location of injury/damage in the brain networks and pathologically are characterized by loss of brain cells. The reason for this loss appears to be an accumulation of misfolded and dysfunctional proteins that trigger apoptotic cell death. The role of alpha-synuclein mutations, its interaction with other proteins and the cellular environment is discussed in the context of selective neuron loss.
December 4, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/29217155/pleiotropic-neuropathological-and-biochemical-alterations-associated-with-myo5a-mutation-in-a-rat-model
#9
Kerstin K Landrock, Patti Sullivan, Heidi Martini-Stoica, David S Goldstein, Brett H Graham, Shinya Yamamoto, Hugo J Bellen, Richard A Gibbs, Rui Chen, Marcello D'Amelio, George Stoica
In this study, we analyze the neuropathological and biochemical alterations involved in the pathogenesis of a neurodegenerative/movement disorder during different developmental stages in juvenile rats with a mutant Myosin5a (Myo5a). In mutant rats, a spontaneous autosomal recessive mutation characterized by the absence of Myo5a protein expression in the brain is associated with a syndrome of locomotor dysfunction, altered coat color, and neuroendocrine abnormalities. Myo5a encodes a myosin motor protein required for transport and proper distribution of subcellular organelles in somatodendritic processes in neurons...
December 4, 2017: Brain Research
https://www.readbyqxmd.com/read/29215752/familial-tauopathy-with-p364s-mapt-mutation-clinical-course-neuropathology-and-ultrastructure-of-neuronal-tau-inclusions
#10
Peter Štrafela, Jerica Pleško, Jožef Magdič, Blaž Koritnik, Andrej Zupan, Damjan Glavač, Mara Bresjanac, Mara Popović
AIMS: This report presents the clinical course, neuropathology and ultrastructure of neuronal tau inclusions of four Slovene relatives with P364S MAPT mutation. METHODS: The clinical history of three out of four P364S MAPT mutation carriers was taken. After formalin fixation, thorough sampling of the central nervous system was followed by paraffin embedding, H&E, Gallyas, Bielschowsky, and immunostaining with AT8, anti-3R, anti-4R tau, anti-Amyloid-β, anti-TDP43, and anti-alpha-synuclein antibodies...
December 7, 2017: Neuropathology and Applied Neurobiology
https://www.readbyqxmd.com/read/29214369/ginkgolide-k-promotes-the-clearance-of-a53t-mutation-alpha-synuclein-in-sh-sy5y-cells
#11
Wenbo Yu, Sheng Chen, Liang Cao, Jie Tang, Wei Xiao, Baoguo Xiao
Alpha-synuclein (α-syn) is associated to Parkinson's disease (PD). The aggregated form of α-syn has potential neurotoxicity. Thus, the clearance of α-syn aggregation is a plausible strategy to delay disease progression of PD. In our study, we found that the treatment of Ginkgolide B (GB) and Ginkgolide K (GK) reduced cell death, and enhanced cell proliferation in SH-SY5Y cells, which overexpressed A53T mutant α-syn. Surprisingly, GK, but not GB, promoted the clearance of A53T α-syn, which can be abolished by autophagy inhibitor 3-methyladenine, indicating that GK-induced autophagy intervened in the clearance of A53T α-syn...
December 6, 2017: Cell Biology and Toxicology
https://www.readbyqxmd.com/read/29205509/cerebrospinal-fluid-plasma-and-saliva-in-the-biofind-study-relationships-among-biomarkers-and-parkinson-s-disease-features
#12
Jennifer G Goldman, Howard Andrews, Amy Amara, Anna Naito, Roy N Alcalay, Leslie M Shaw, Peggy Taylor, Tao Xie, Paul Tuite, Claire Henchcliffe, Penelope Hogarth, Samuel Frank, Marie-Helene Saint-Hilaire, Mark Frasier, Vanessa Arnedo, Alyssa N Reimer, Margaret Sutherland, Christine Swanson-Fischer, Katrina Gwinn, Un Jung Kang
OBJECTIVE: Examine relationships among neurodegenerative biomarkers and PD motor and nonmotor symptoms. BACKGROUND: CSF alpha-synuclein is decreased in PD versus healthy controls, but whether plasma and saliva alpha-synuclein differentiate these groups is controversial. Correlations of alpha-synuclein among biofluids (CSF, plasma, saliva) or biomarkers (eg, beta-amyloid, tau [total, phosphorylated]) are not fully understood. The relationships of these biomarkers with PD clinical features remain unclear...
December 4, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/29201595/microbes-tickling-your-tummy-the-importance-of-the-gut-brain-axis-in-parkinson-s-disease
#13
REVIEW
Paula Perez-Pardo, Mitch Hartog, Johan Garssen, Aletta D Kraneveld
Purpose of Review: Patients suffering from Parkinson's disease (PD) are known to experience gastrointestinal dysfunction that might precede the onset of motor symptoms by several years. Evidence suggests an important role of the gut-brain axis in PD pathogenesis. These interactions might be essentially influenced by the gut microbiota. Here, we review recent findings supporting that changes in the gut microbiota composition might be a trigger for inflammation contributing to neurodegeneration in PD...
2017: Current Behavioral Neuroscience Reports
https://www.readbyqxmd.com/read/29198173/autophagy-inhibition-promotes-snca-alpha-synuclein-release-and-transfer-via-extracellular-vesicles-with-a-hybrid-autophagosome-exosome-like-phenotype
#14
Georgia Minakaki, Stefanie Menges, Agnes Kittel, Evangelia Emmanouilidou, Iris Schaeffner, Katalin Barkovits, Anna Bergmann, Edward Rockenstein, Anthony Adame, Franz Marxreiter, Brit Mollenhauer, Douglas Galasko, Edit Irén Buzás, Ursula Schlötzer-Schrehardt, Katrin Marcus, Wei Xiang, Dieter Chichung Lie, Kostas Vekrellis, Eliezer Masliah, Jürgen Winkler, Jochen Klucken
The autophagy-lysosome pathway (ALP) regulates intracellular homeostasis of the cytosolic protein SNCA/alpha-synuclein and is impaired in synucleinopathies, including Parkinson disease and dementia with Lewy bodies (DLB). Emerging evidence suggests that ALP influences SNCA release, but the underlying cellular mechanisms are not well understood. Several studies identified SNCA in exosome/extracellular vesicle (EV) fractions. EVs are generated in the multivesicular body compartment and either released upon its fusion with the plasma membrane, or cleared via the ALP...
December 4, 2017: Autophagy
https://www.readbyqxmd.com/read/29198021/alpha-synuclein-aggregation-ubiquitin-proteasome-system-impairment-and-l-dopa-response-in-zinc-induced-parkinsonism-resemblance-to-sporadic-parkinson-s-disease
#15
Vinod Kumar, Deepali Singh, Brajesh Kumar Singh, Shweta Singh, Namrata Mittra, Rakesh Roshan Jha, Devendra Kumar Patel, Chetna Singh
Alpha-synuclein (α-synuclein) aggregation and impairment of the Ubiquitin proteasome system (UPS) are implicated in Parkinson's disease (PD) pathogenesis. While zinc (Zn) induces dopaminergic neurodegeneration resulting in PD phenotype, its effect on protein aggregation and UPS has not yet been deciphered. The current study investigated the role of α-synuclein aggregation and UPS in Zn-induced Parkinsonism. Additionally, levodopa (L-Dopa) response was assessed in Zn-induced Parkinsonian model to establish its closeness with idiopathic PD...
December 2, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/29196808/propagation-of-alpha-synuclein-pathology-from-the-olfactory-bulb-possible-role-in-the-pathogenesis-of-dementia-with-lewy-bodies
#16
REVIEW
María Graciela Cersosimo
Olfactory limbic structures, like the amygdala, the entorhinal, and the piriform cortices, are closely involved in cognitive processes. Thus, besides olfactory dysfunctions, it is conceivable that the compromise of these structures can lead to cognitive impairment. The olfactory bulb is affected by alpha-synuclein pathology in almost all cases of both Parkinson's disease and dementia with Lewy bodies. The clinical distinction between these disorders relies on the timing in the appearance of dementia in relationship to motor symptoms...
December 1, 2017: Cell and Tissue Research
https://www.readbyqxmd.com/read/29196214/the-lysosomal-enzyme-alpha-galactosidase-a-is-deficient-in-parkinson-s-disease-brain-in-association-with-the-pathologic-accumulation-of-alpha-synuclein
#17
Michael P Nelson, Michel Boutin, Tonia E Tse, Hailin Lu, Emily D Haley, Xiaosen Ouyang, Jianhua Zhang, Christiane Auray-Blais, John J Shacka
The aberrant accumulation of alpha-synuclein (α-syn) is believed to contribute to the onset and pathogenesis of Parkinson's disease (PD). The autophagy-lysosome pathway (ALP) is responsible for the high capacity clearance of α-syn. ALP dysfunction is documented in PD and pre-clinical evidence suggests that inhibiting the ALP promotes the pathological accumulation of α-syn. We previously identified the pathological accumulation of α-syn in the brains of mice deficient for the soluble lysosomal enzyme alpha-Galactosidase A (α-Gal A), a member of the glycosphingolipid metabolism pathway...
December 2, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/29193611/effect-of-the-cross-talk-between-autophagy-and-endoplasmic-reticulum-stress-on-mn-induced-alpha-synuclein-oligomerization
#18
Chang Liu, Dong-Ying Yan, Xuan Tan, Zhuo Ma, Can Wang, Yu Deng, Wei Liu, Tian-Yao Yang, Zhao-Fa Xu, Bin Xu
Overexposure to manganese (Mn) has been known to induce alpha-synuclein (α-Syn) oligomerization, which is degraded mainly depending on endoplasmic reticulum stress (ER stress) and autophagy pathways. However, little data reported the cross-talk between ER stress and autophagy on Mn-induced α-Syn oligomerization. To explore the relationship between ER stress and autophagy, we used 4-phenylbutyric acid (4-PBA, the ER stress inhibitor), rapamycin (Rap, autophagy activator) and 3-methyladenine (3-MA, autophagy inhibitor) in mice model of manganism...
November 29, 2017: Environmental Toxicology
https://www.readbyqxmd.com/read/29189256/enteric-pathologic-manifestations-of-alpha-synucleinopathies
#19
Michael Punsoni, Joseph H Friedman, Murray Resnick, John E Donahue, Dong Fang Yang, Edward G Stopa
BACKGROUND: Gastrointestinal (GI) symptoms are common in Parkinson disease (PD), often preceding neurological manifestations; however, early diagnostic utility of GI biopsies remains controversial. Studies suggest aberrant deposition of alpha-synuclein (α-syn) follows step-wise progression in central nervous system though histologic interpretation of normal and aberrant staining patterns have shown variable results. This study examines whether GI α-syn mRNA expression combined with standard α-syn immunohistochemical staining enhance the role of GI biopsy in PD...
November 20, 2017: Applied Immunohistochemistry & Molecular Morphology: AIMM
https://www.readbyqxmd.com/read/29189163/alpha-synuclein-proteotoxicity-and-parkinson-s-disease-search-for-neuroprotective-therapy
#20
Upasana Ganguly, Sankha Shubhra Chakrabarti, Upinder Kaur, Anwesha Mukherjee, Sasanka Chakrabarti
There is a growing body of evidence in animal and cell based models of Parkinson's disease (PD) to suggest that overexpression and / or abnormal accumulation and aggregation of α-synuclein can trigger neuronal death. This important role of α-synuclein in PD pathogenesis is supported by the fact that duplication, triplication and mutations of α-synuclein gene cause familial forms of PD. The overexpression and accumulation of α-synuclein within neurons may involve both transcriptional and post-transcriptional mechanisms including a decreased degradation of the protein through proteasomal or autophagic processes...
November 28, 2017: Current Neuropharmacology
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