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https://www.readbyqxmd.com/read/28225193/human-neural-progenitor-transplantation-rescues-behavior-and-reduces-%C3%AE-synuclein-in-a-transgenic-model-of-dementia-with-lewy-bodies
#1
Natalie R S Goldberg, Samuel E Marsh, Joseph Ochaba, Brandon C Shelley, Hayk Davtyan, Leslie M Thompson, Joan S Steffan, Clive N Svendsen, Mathew Blurton-Jones
Synucleinopathies are a group of neurodegenerative disorders sharing the common feature of misfolding and accumulation of the presynaptic protein α-synuclein (α-syn) into insoluble aggregates. Within this diverse group, Dementia with Lewy Bodies (DLB) is characterized by the aberrant accumulation of α-syn in cortical, hippocampal, and brainstem neurons, resulting in multiple cellular stressors that particularly impair dopamine and glutamate neurotransmission and related motor and cognitive function. Recent studies show that murine neural stem cell (NSC) transplantation can improve cognitive or motor function in transgenic models of Alzheimer's and Huntington's disease, and DLB...
February 22, 2017: Stem Cells Translational Medicine
https://www.readbyqxmd.com/read/28224980/alpha-synuclein-prevents-the-formation-of-spherical-mitochondria-and-apoptosis-under-oxidative-stress
#2
Stefanie Menges, Georgia Minakaki, Patrick M Schaefer, Holger Meixner, Iryna Prots, Ursula Schlötzer-Schrehardt, Kristina Friedland, Beate Winner, Tiago F Outeiro, Konstanze F Winklhofer, Christine A F von Arnim, Wei Xiang, Jürgen Winkler, Jochen Klucken
Oxidative stress (OS), mitochondrial dysfunction, and dysregulation of alpha-synuclein (aSyn) homeostasis are key pathogenic factors in Parkinson's disease. Nevertheless, the role of aSyn in mitochondrial physiology remains elusive. Thus, we addressed the impact of aSyn specifically on mitochondrial response to OS in neural cells. We characterize a distinct type of mitochondrial fragmentation, following H2O2 or 6-OHDA-induced OS, defined by spherically-shaped and hyperpolarized mitochondria, termed "mitospheres"...
February 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28223512/glucosylceramide-synthase-inhibition-alleviates-aberrations-in-synucleinopathy-models
#3
S Pablo Sardi, Catherine Viel, Jennifer Clarke, Christopher M Treleaven, Amy M Richards, Hyejung Park, Maureen A Olszewski, James C Dodge, John Marshall, Elina Makino, Bing Wang, Richard L Sidman, Seng H Cheng, Lamya S Shihabuddin
Mutations in the glucocerebrosidase gene (GBA) confer a heightened risk of developing Parkinson's disease (PD) and other synucleinopathies, resulting in a lower age of onset and exacerbating disease progression. However, the precise mechanisms by which mutations in GBA increase PD risk and accelerate its progression remain unclear. Here, we investigated the merits of glucosylceramide synthase (GCS) inhibition as a potential treatment for synucleinopathies. Two murine models of synucleinopathy (a Gaucher-related synucleinopathy model, Gba(D409V/D409V) and a A53T-α-synuclein overexpressing model harboring wild-type alleles of GBA, A53T-SNCA mouse model) were exposed to a brain-penetrant GCS inhibitor, GZ667161...
February 21, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28222538/vps35-the-retromer-complex-and-parkinson-s-disease
#4
Erin T Williams, Xi Chen, Darren J Moore
Mutations in the vacuolar protein sorting 35 ortholog (VPS35) gene encoding a core component of the retromer complex, have recently emerged as a new cause of late-onset, autosomal dominant familial Parkinson's disease (PD). A single missense mutation, AspD620Asn (D620N), has so far been unambiguously identified to cause PD in multiple individuals and families worldwide. The exact molecular mechanism(s) by which VPS35 mutations induce progressive neurodegeneration in PD are not yet known. Understanding these mechanisms, as well as the perturbed cellular pathways downstream of mutant VPS35, is important for the development of appropriate therapeutic strategies...
February 8, 2017: Journal of Parkinson's Disease
https://www.readbyqxmd.com/read/28220836/nucleobindin-1-binds-to-multiple-types-of-pre-fibrillar-amyloid-and-inhibits-fibrillization
#5
Alessandra Bonito-Oliva, Shahar Barbash, Thomas P Sakmar, W Vallen Graham
During amyloid fibril formation, amyloidogenic polypeptides misfold and self assemble into soluble pre-fibrillar aggregates, i.e., protofibrils, which elongate and mature into insoluble fibrillar aggregates. An emerging class of chaperones, chaperone-like amyloid binding proteins (CLABPs), has been shown to interfere with aggregation of particular misfolded amyloid peptides or proteins. We have discovered that the calcium-binding protein nuclebindin-1 (NUCB1) is a novel CLABP. We show that NUCB1 inhibits aggregation of islet-amyloid polypeptide associated with type 2 diabetes mellitus, a-synuclein associated with Parkinson's disease, transthyretin V30M mutant associated with familial amyloid polyneuropathy, and Aβ42 associated with Alzheimer's disease by stabilizing their respective protofibril intermediates...
February 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28218461/targeting-%C3%AE-synuclein-as-a-therapy-for-parkinson-s-disease-the-battle-begins
#6
C Warren Olanow, Jeffrey H Kordower
No abstract text is available yet for this article.
February 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28218457/whether-the-dissociation-between-toxicity-and-%C3%AE-synuclein-inclusion-will-be-a-possible-therapy-for-parkinson-s-disease-or-not
#7
Reyhane Ebrahimi, Soheila Sobhani, Maryam Abbastabar
No abstract text is available yet for this article.
February 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28218419/alpha-synuclein-fibrils-propagate-through-tunneling-nanotubes
#8
Shinya Okuda, Norihito Uemura, Ryosuke Takahashi
No abstract text is available yet for this article.
February 20, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28217771/detection-inhibition-and-disintegration-of-amyloid-fibrils-the-role-of-optical-probes-and-macrocyclic-receptors
#9
Achikanath C Bhasikuttan, Jyotirmayee Mohanty
Amyloid fibrils are formed by the aberrant aggregation of proteins into highly ordered β-sheet structures and are believed to be the root cause of several neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Prion diseases, etc. and have been the subject of extensive biochemical, biophysical and clinical studies. Developing methods for the early detection of fibril formation using optical spectroscopic techniques and inhibition/disintegration of amyloid fibrils/plaques by introducing small molecules have been a major challenge to establish a clinically facile therapeutic intervention to combat these neurodegenerative diseases...
February 20, 2017: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/28217760/sleep-in-alzheimer-s-disease-beyond-amyloid
#10
Jerrah Holth, Tirth Patel, David M Holtzman
Sleep disorders are prevalent in Alzheimer's disease (AD) and a major cause of institutionalization. Like AD pathology, sleep abnormalities can appear years before cognitive decline and may be predictive of dementia. A bidirectional relationship between sleep and amyloid β (Aβ) has been well established with disturbed sleep and increased wakefulness leading to increased Aβ production and decreased Aβ clearance; whereas Aβ deposition is associated with increased wakefulness and sleep disturbances. Aβ fluctuates with the sleep wake cycle and is higher during wakefulness and lower during sleep...
January 2017: Neurobiology of Sleep and Circadian Rhythms
https://www.readbyqxmd.com/read/28216145/a-human-neural-crest-stem-cell-derived-dopaminergic-neuronal-model-recapitulates-biochemical-abnormalities-in-gba1-mutation-carriers
#11
Shi-Yu Yang, Michelle Beavan, Kai-Yin Chau, Jan-Willem Taanman, Anthony H V Schapira
Numerically the most important risk factor for the development of Parkinson's disease (PD) is the presence of mutations in the glucocerebrosidase GBA1 gene. In vitro and in vivo studies show that GBA1 mutations reduce glucocerebrosidase (GCase) activity and are associated with increased α-synuclein levels, reflecting similar changes seen in idiopathic PD brain. We have developed a neural crest stem cell-derived dopaminergic neuronal model that recapitulates biochemical abnormalities in GBA1 mutation-associated PD...
February 15, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28214749/impairment-in-the-mesohippocampal-dopamine-circuit-following-exposure-to-the-brominated-flame-retardant-hbcdd
#12
Camille Pham-Lake, Elizabeth B Aronoff, Chad R Camp, Aimee Vester, Sam J Peters, W Michael Caudle
Many chemicals have been used to increase the safety of consumer products by reducing their flammability and risk for ignition. Recent focus on brominated flame retardants, such as polybrominated diphenyl ethers (PBDEs) has shown them to contribute to neurobehavioral deficits in children, including learning and memory. As the manufacture and use of PBDEs have been reduced, replacement chemicals, such as hexabromocyclododecane (HBCDD) have been substituted. Our current study evaluated the neurotoxicity of HBCDD, concentrating on dopaminergic innervation to the hippocampus...
February 4, 2017: Environmental Toxicology and Pharmacology
https://www.readbyqxmd.com/read/28214539/lumbee-traditional-medicine-neuroprotective-activities-of-medicinal-plants-used-to-treat-parkinson-s-disease-related-symptoms
#13
Aurélie de Rus Jacquet, Michael Timmers, Sin Ying Ma, Andrew Thieme, George P McCabe, Jay Hansford C Vest, Mary Ann Lila, Jean-Christophe Rochet
ETHNOPHARMACOLOGICAL RELEVANCE: Parkinson's disease (PD) is a neurodegenerative disorder characterized by a loss of dopaminergic neurons in the substantia nigra pars compacta and the presence in surviving neurons of Lewy body inclusions enriched with aggregated forms of the presynaptic protein α-synuclein (aSyn). Although current therapies provide temporary symptomatic relief, they do not slow the underlying neurodegeneration in the midbrain. In this study, we analyzed contemporary herbal medicinal practices used by members of the Lumbee tribe to treat PD-related symptoms, in an effort to identify safe and effective herbal medicines to treat PD...
February 15, 2017: Journal of Ethnopharmacology
https://www.readbyqxmd.com/read/28214264/identification-of-candidate-cerebrospinal-fluid-biomarkers-in-parkinsonism-using-quantitative-proteomics
#14
N K Magdalinou, A J Noyce, R Pinto, E Lindstrom, J Holmén-Larsson, M Holtta, K Blennow, H R Morris, T Skillbäck, T T Warner, A J Lees, I Pike, M Ward, H Zetterberg, J Gobom
INTRODUCTION: Neurodegenerative parkinsonian syndromes have significant clinical and pathological overlap, making early diagnosis difficult. Cerebrospinal fluid (CSF) biomarkers may aid the differentiation of these disorders, but other than α-synuclein and neurofilament light chain protein, which have limited diagnostic power, specific protein biomarkers remain elusive. OBJECTIVES: To study disease mechanisms and identify possible CSF diagnostic biomarkers through discovery proteomics, which discriminate parkinsonian syndromes from healthy controls...
January 31, 2017: Parkinsonism & related Disorders
https://www.readbyqxmd.com/read/28213437/%C3%AE-synuclein-multiple-system-atrophy-prions
#15
Amanda L Woerman, Joel C Watts, Atsushi Aoyagi, Kurt Giles, Lefkos T Middleton, Stanley B Prusiner
Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disease arising from the misfolding and accumulation of the protein α-synuclein in oligodendrocytes, where it forms glial cytoplasmic inclusions (GCIs). Several years of studying synthetic α-synuclein fibrils has provided critical insight into the ability of α-synuclein to template endogenous protein misfolding, giving rise to fibrillar structures capable of propagating from cell to cell. However, more recent studies with MSA-derived α-synuclein aggregates have shown that they have a similar ability to undergo template-directed propagation, like PrP prions...
February 17, 2017: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/28213435/genetics-of-synucleinopathies
#16
Robert L Nussbaum
Parkinson's disease (PD), diffuse Lewy body disease (DLBD), and multiple system atrophy (MSA) constitute the three major neurodegenerative disorders referred to as synucleinopathies because both genetic and pathological results implicate the α-synuclein protein in their pathogenesis. PD and DLBD are recognized as closely related diseases with substantial clinical and pathological overlap. MSA, on the other hand, has a distinctive clinical presentation and neuropathological profile. In this review, we will summarize the evidence linking α-synuclein to these three disorders...
February 17, 2017: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/28213071/pla2g6-accumulates-in-lewy-bodies-in-park14-and-idiopathic-parkinson-s-disease
#17
Yasuo Miki, Kunikazu Tanji, Fumiaki Mori, Akiyoshi Kakita, Hitoshi Takahashi, Koichi Wakabayashi
The histopathological hallmark of Parkinson's disease (PD) and dementia with Lewy bodies (DLB) is the occurrence of insoluble fibrillary aggregates known as Lewy bodies, in which phosphorylated α-synuclein (α-syn) is a major component. To date, familial PD-linked gene products, including α-syn, parkin, PINK-1, DJ-1 and LRRK2, are known to be involved in Lewy body formation. Phospholipase A2, group VI (PLA2G6) is the causative gene for PARK14-linked parkinsonism (PARK14), a familial form of juvenile-onset dystonia parkinsonism...
February 14, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28212984/hiv-1-vpr-disrupts-mitochondria-axonal-transport-and-accelerates-neuronal-aging
#18
Ying Wang, Maryline Santerre, Italo Tempera, Kayla Martin, Ruma Mukerjee, Bassel E Sawaya
Disruption of mitochondria axonal transport, essential for the maintenance of synaptic and neuronal integrity and function, has been identified in neurodegenerative diseases. Whether HIV-1 viral proteins affect mitochondria axonal transport is unknown, albeit HIV-associated neurocognitive disorders occur in around half of the patients living with HIV. Therefore, we sought to examine the effect of HIV-1 viral protein R (Vpr) on mitochondria axonal transport. Using mice primary neuronal cultures, we demonstrated that 4-day Vpr treatment reduced the ratio of moving mitochondria associated with (i) less energy (ATP) supply, (ii) reduction in Miro-1 and (iii) increase of α-synuclein which led to loss of microtubule stability as demonstrated by inconsecutive distribution of acetylated α-tubulin along the axons...
February 14, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28212433/elevated-gm3-plasma-concentration-in-idiopathic-parkinson-s-disease-a-lipidomic-analysis
#19
Robin B Chan, Adler J Perotte, Bowen Zhou, Christopher Liong, Evan J Shorr, Karen S Marder, Un J Kang, Cheryl H Waters, Oren A Levy, Yimeng Xu, Hong Bin Shim, Itsik Pe'er, Gilbert Di Paolo, Roy N Alcalay
Parkinson's disease (PD) is a common neurodegenerative disease whose pathological hallmark is the accumulation of intracellular α-synuclein aggregates in Lewy bodies. Lipid metabolism dysregulation may play a significant role in PD pathogenesis; however, large plasma lipidomic studies in PD are lacking. In the current study, we analyzed the lipidomic profile of plasma obtained from 150 idiopathic PD patients and 100 controls, taken from the 'Spot' study at Columbia University Medical Center in New York. Our mass spectrometry based analytical panel consisted of 520 lipid species from 39 lipid subclasses including all major classes of glycerophospholipids, sphingolipids, glycerolipids and sterols...
2017: PloS One
https://www.readbyqxmd.com/read/28208742/aav-vector-mediated-gene-delivery-to-substantia-nigra-dopamine-neurons-implications-for-gene-therapy-and-disease-models
#20
REVIEW
Katrina Albert, Merja H Voutilainen, Andrii Domanskyi, Mikko Airavaara
Gene delivery using adeno-associated virus (AAV) vectors is a widely used method to transduce neurons in the brain, especially due to its safety, efficacy, and long-lasting expression. In addition, by varying AAV serotype, promotor, and titer, it is possible to affect the cell specificity of expression or the expression levels of the protein of interest. Dopamine neurons in the substantia nigra projecting to the striatum, comprising the nigrostriatal pathway, are involved in movement control and degenerate in Parkinson's disease...
February 8, 2017: Genes
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