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https://www.readbyqxmd.com/read/27405155/-autophagy-pathways-and-key-drug-targets-in-parkinson-s-disease
#1
REVIEW
Liang Ouyang, Lan Zhang, Bo Liu
Parkinson's disease (PD) is a common neurodegenerative disorder associated with aging. Great progresses have been made toward understanding the pathogenesis over the past decades. It seems that both genetic factors and environmental factors contribute to PD, while the precise pathogenesis still remains unknown. Recently, increasing evidence has suggested that autophagy dysregulation is closely related to PD. Dysregulation of the autophagic pathways has been observed in the brains of PD patients or in animal models of PD, and a number of PD-associated proteins, such as a-synuclein, Parkin and PINK1, were found to involve in autophagy, suggesting a link between autophagy and pathogenesis of PD...
January 2016: Yao Xue Xue Bao, Acta Pharmaceutica Sinica
https://www.readbyqxmd.com/read/27240409/parkinson-s-disease-assay-of-phosphorylated-%C3%AE-synuclein-in-skin-biopsy-for-early-diagnosis-and-association-with-melanoma
#2
Andrei Surguchov
Parkinson's disease (PD) is a degenerative disorder of the central nervous system, in which a small naturally unfolded protein α-synuclein plays an essential role. α-Synuclein belongs to a synuclein family comprising three members: α, β, and γ-synucleins associated with neurodegenerative and neoplastic diseases and involved in development. Several studies revealed that α-synuclein is present not only in the brain, but also in the skin and other peripheral tissues. This finding open a new approach to PD diagnosis based on the assay of α-synuclein from a biological sample of a living patient...
2016: Brain Sciences
https://www.readbyqxmd.com/read/26972727/alteration-of-structure-and-aggregation-of-a-synuclein-by-familial-parkinson-s-disease-associated-mutations
#3
Shruti Sahay, Dhiman Ghosh, Pardeep K Singh, Samir K Maji
a-Synuclein (a-Syn) aggregation is directly associated with Parkinson's disease (PD) pathogenesis. In vitro aggregation and in vivo animal model studies of a-Syn recapitulate many features of the disease pathogenesis. Six familial PD associated mutations of a-Syn have been discovered; many of which are associated with early onset PD. Three of PD associated mutations have been shown to accelerate the a-Syn aggregation, whereas other three are shown to delay the aggregation kinetics. The membrane binding studies also suggest that few of these PD mutants strongly bind to synthetic membrane vesicles, while others are shown to have attenuated membrane binding ability...
March 14, 2016: Current Protein & Peptide Science
https://www.readbyqxmd.com/read/26655601/broad-neutralization-of-calcium-permeable-amyloid-pore-channels-with-a-chimeric-alzheimer-parkinson-peptide-targeting-brain-gangliosides
#4
Coralie Di Scala, Nouara Yahi, Alessandra Flores, Sonia Boutemeur, Nazim Kourdougli, Henri Chahinian, Jacques Fantini
Growing evidence supports a role for brain gangliosides in the pathogenesis of neurodegenerative diseases including Alzheimer's and Parkinson's. Recently we deciphered the ganglioside-recognition code controlling specific ganglioside binding to Alzheimer's β-amyloid (Aβ1-42) peptide and Parkinson's disease-associated protein α-synuclein. Cracking this code allowed us to engineer a short chimeric Aβ/α-synuclein peptide that recognizes all brain gangliosides. Here we show that ganglioside-deprived neural cells do no longer sustain the formation of zinc-sensitive amyloid pore channels induced by either Aβ1-42 or α-synuclein, as assessed by single-cell Ca(2+) fluorescence microscopy...
February 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/26389963/camp-inhibits-cytoplasmic-phospholipase-a%C3%A2-and-protects-neurons-against-amyloid-%C3%AE-induced-synapse-damage
#5
Clive Bate, Alun Williams
A key event in Alzheimer's disease (AD) is the production of amyloid-β (Aβ) peptides and the loss of synapses. In cultured neurons Aβ triggered synapse damage as measured by the loss of synaptic proteins. α-synuclein (αSN), aggregates of which accumulate in Parkinson's disease, also caused synapse damage. Synapse damage was associated with activation of cytoplasmic phospholipase A₂ (cPLA₂), an enzyme that regulates synapse function and structure, and the production of prostaglandin (PG) E₂. In synaptosomes PGE₂ increased concentrations of cyclic adenosine monophosphate (cAMP) which suppressed the activation of cPLA₂ demonstrating an inhibitory feedback system...
2015: Biology
https://www.readbyqxmd.com/read/26388395/mitochondrial-dysfunction-associated-with-glucocerebrosidase-deficiency
#6
Matthew E Gegg, Anthony H V Schapira
The lysosomal hydrolase glucocerebrosidase (GCase) is encoded for by the GBA gene. Homozygous GBA mutations cause Gaucher disease (GD), a lysosomal storage disorder. Furthermore, homozygous and heterozygous GBA mutations are numerically the greatest genetic risk factor for developing Parkinson's disease (PD), the second most common neurodegenerative disorder. The loss of GCase activity results in impairment of the autophagy-lysosome pathway (ALP), which is required for the degradation of macromolecules and damaged organelles...
June 2016: Neurobiology of Disease
https://www.readbyqxmd.com/read/26385697/the-neuroprotective-role-of-ferrostatin-1-under-rotenone-induced-oxidative-stress-in-dopaminergic-neuroblastoma-cells
#7
Parijat Kabiraj, Carlos A Valenzuela, Jose E Marin, David A Ramirez, Lois Mendez, Michael S Hwang, Armando Varela-Ramirez, Karine Fenelon, Mahesh Narayan, Rachid Skouta
Endoplasmic reticulum (ER) proteins including protein disulfide isomerase (PDI) are playing crucial roles in maintaining appropriate protein folding. Under nitrosative stress, an excess of nitric oxide (NO) radical species induced the S-nitrosylation of PDI cysteines which eliminate its isomerase and oxidoreductase capabilities. In addition, the S-nitrosylation-PDI complex is the cause of aggregation especially of the α-synuclein (α-syn) protein (accumulation of Lewy-body aggregates). We recently identified a potent antioxidant small molecule, Ferrostatin-1 (Fer-1), that was able to inhibit a non-apoptotic cell death named ferroptosis...
October 2015: Protein Journal
https://www.readbyqxmd.com/read/26382574/parkinson-s-disease-anxious-depression-and-serotonin-zooming-in-on-hippocampal-neurogenesis
#8
EDITORIAL
Robert Blum, Klaus-Peter Lesch
No abstract text is available yet for this article.
November 2015: Journal of Neurochemistry
https://www.readbyqxmd.com/read/26381815/sensitive-western-blotting-for-detection-of-endogenous-ser129-phosphorylated-%C3%AE-synuclein-in-intracellular-and-extracellular-spaces
#9
Asuka Sasaki, Shigeki Arawaka, Hiroyasu Sato, Takeo Kato
α-Synuclein deposited in Lewy bodies, a pathological hallmark of Parkinson's disease (PD), is highly phosphorylated at serine 129 (Ser129). In contrast, there is very little Ser129-phosphorylated α-synuclein in the normal brains. This difference suggests that Ser129-phosphorylation is involved in neurodegenerative processes of PD. However, the role of this modification remains unclear. One limiting factor for relevant biochemical analyses is that it is difficult to detect endogenous Ser129-phosphorylated α-synuclein by western blotting, because α-synuclein monomers detached from the transferred membrane during incubation...
2015: Scientific Reports
https://www.readbyqxmd.com/read/26381411/oligomerization-and-membrane-binding-properties-of-covalent-adducts-formed-by-the-interaction-of-%C3%AE-synuclein-with-the-toxic-dopamine-metabolite-3-4-dihydroxyphenylacetaldehyde-dopal
#10
Cristian Follmer, Eduardo Coelho-Cerqueira, Danilo Y Yatabe-Franco, Gabriel D T Araujo, Anderson S Pinheiro, Gilberto B Domont, David Eliezer
Oxidative deamination of dopamine produces the highly toxic aldehyde 3,4-dihydroxyphenylacetaldehyde (DOPAL), enhanced production of which is found in post-mortem brains of Parkinson disease patients. When injected into the substantia nigra of rat brains, DOPAL causes the loss of dopaminergic neurons accompanied by the accumulation of potentially toxic oligomers of the presynaptic protein α-synuclein (aS), potentially explaining the synergistic toxicity described for dopamine metabolism and aS aggregation...
November 13, 2015: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/26378986/drugs-that-bind-to-%C3%AE-synuclein-neuroprotective-or-neurotoxic
#11
Joe Kakish, Dongsoo Lee, Jeremy S Lee
The misfolding of α-synuclein is a critical event in the death of dopaminergic neurons and the progression of Parkinson's disease. Drugs that bind to α-synuclein and form a loop structure between the N- and C-terminus tend to be neuroprotective, whereas others that cause a more compact structure tend to be neurotoxic. The binding of several natural products and other drugs that are involved in dopamine metabolism were investigated by nanopore analysis and isothermal titration calorimetry. The antinausea drugs, cinnarizine and metoclopramide, do not bind to α-synuclein, whereas amphetamine and the herbicides, paraquat and rotenone, bind tightly and cause α-synuclein to adopt a more compact conformation...
December 16, 2015: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/26378614/gba-deficiency-promotes-snca-%C3%AE-synuclein-accumulation-through-autophagic-inhibition-by-inactivated-ppp2a
#12
Ting-Ting Du, Le Wang, Chun-Li Duan, Ling-Ling Lu, Jian-Liang Zhang, Ge Gao, Xiao-Bo Qiu, Xiao-Min Wang, Hui Yang
Loss-of-function mutations in the gene encoding GBA (glucocerebrosidase, β, acid), the enzyme deficient in the lysosomal storage disorder Gaucher disease, elevate the risk of Parkinson disease (PD), which is characterized by the misprocessing of SNCA/α-synuclein. However, the mechanistic link between GBA deficiency and SNCA accumulation remains poorly understood. In this study, we found that loss of GBA function resulted in increased levels of SNCA via inhibition of the autophagic pathway in SK-N-SH neuroblastoma cells, primary rat cortical neurons, or the rat striatum...
2015: Autophagy
https://www.readbyqxmd.com/read/26376862/glucocerebrosidase-1-deficient-danio-rerio-mirror-key-pathological-aspects-of-human-gaucher-disease-and-provide-evidence-of-early-microglial-activation-preceding-alpha-synuclein-independent-neuronal-cell-death
#13
Marcus Keatinge, Hai Bui, Aswin Menke, Yu-Chia Chen, Anna M Sokol, Qing Bai, Felix Ellett, Marc Da Costa, Derek Burke, Matthew Gegg, Lisa Trollope, Thomas Payne, Aimee McTighe, Heather Mortiboys, Sarah de Jager, Hugh Nuthall, Ming-Shang Kuo, Angeleen Fleming, Anthony H V Schapira, Stephen A Renshaw, J Robin Highley, Agnieszka Chacinska, Pertti Panula, Edward A Burton, Michael J O'Neill, Oliver Bandmann
Autosomal recessively inherited glucocerebrosidase 1 (GBA1) mutations cause the lysosomal storage disorder Gaucher's disease (GD). Heterozygous GBA1 mutations (GBA1(+/-)) are the most common risk factor for Parkinson's disease (PD). Previous studies typically focused on the interaction between the reduction of glucocerebrosidase (enzymatic) activity in GBA1(+/-) carriers and alpha-synuclein-mediated neurotoxicity. However, it is unclear whether other mechanisms also contribute to the increased risk of PD in GBA1(+/-) carriers...
December 1, 2015: Human Molecular Genetics
https://www.readbyqxmd.com/read/26376455/cdk5-at-crossroads-of-protein-oligomerization-in-neurodegenerative-diseases-facts-and-hypotheses
#14
REVIEW
Anna Wilkaniec, Grzegorz A Czapski, Agata Adamczyk
Cyclin-dependent kinase 5 (Cdk5) is involved in proper neurodevelopment and brain function and serves as a switch between neuronal survival and death. Overactivation of Cdk5 is associated with many neurodegenerative disorders such as Alzheimer's or Parkinson's diseases. It is believed that in those diseases Cdk5 may be an important link between disease-initiating factors and cell death effectors. A common hallmark of neurodegenerative disorders is incorrect folding of specific proteins, thus leading to their intra- and extracellular accumulation in the nervous system...
January 2016: Journal of Neurochemistry
https://www.readbyqxmd.com/read/26375494/ceftriaxone-attenuates-acute-cocaine-evoked-dopaminergic-neurotransmission-in-the-nucleus-accumbens-of-the-rat
#15
J L Barr, B A Rasmussen, C S Tallarida, J L Scholl, G L Forster, E M Unterwald, S M Rawls
BACKGROUND AND PURPOSE: Ceftriaxone is a β-lactam antibiotic and glutamate transporter activator that reduces the reinforcing effects of psychostimulants. Ceftriaxone also reduces locomotor activation following acute psychostimulant exposure, suggesting that alterations in dopamine transmission in the nucleus accumbens contribute to its mechanism of action. In the present studies we tested the hypothesis that pretreatment with ceftriaxone disrupts acute cocaine-evoked dopaminergic neurotransmission in the nucleus accumbens...
November 2015: British Journal of Pharmacology
https://www.readbyqxmd.com/read/26374630/distribution-of-%C3%AE-synuclein-in-the-spinal-cord-and-dorsal-root-ganglia-in-an-autopsy-cohort-of-elderly-persons
#16
Hiroyuki Sumikura, Masaki Takao, Hiroyuki Hatsuta, Shinji Ito, Yuta Nakano, Akiko Uchino, Akane Nogami, Yuko Saito, Hideki Mochizuki, Shigeo Murayama
BACKGROUND: Lewy body-related α-synucleinopathy (LBAS, the abnormal accumulation of pathologic α-synuclein) is found in the central and peripheral nervous systems, including the spinal cord, dorsal root ganglia, and sympathetic ganglia, of Parkinson's disease patients. However, few studies have focused on the distribution of LBAS in the spinal cord, primary sensory neurons, and preganglionic sympathetic nerves. RESULTS: We analyzed 265 consecutive subjects with LBAS who underwent autopsy at a general geriatric hospital...
2015: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/26372625/interaction-between-basal-ganglia-and-limbic-circuits-in-learning-and-memory-processes
#17
REVIEW
Paolo Calabresi, Barbara Picconi, Alessandro Tozzi, Veronica Ghiglieri
Hippocampus and striatum play distinctive roles in memory processes since declarative and non-declarative memory systems may act independently. However, hippocampus and striatum can also be engaged to function in parallel as part of a dynamic system to integrate previous experience and adjust behavioral responses. In these structures the formation, storage, and retrieval of memory require a synaptic mechanism that is able to integrate multiple signals and to translate them into persistent molecular traces at both the corticostriatal and hippocampal/limbic synapses...
January 2016: Parkinsonism & related Disorders
https://www.readbyqxmd.com/read/26367469/apocyanin-nadph-oxidase-inhibitor-prevents-lipopolysaccharide-induced-%C3%AE-synuclein-aggregation-and-ameliorates-motor-function-deficits-in-rats-possible-role-of-biochemical-and-inflammatory-alterations
#18
Neha Sharma, Monika Kapoor, Bimla Nehru
Parkinson's disease (PD), is an age-related, progressive neurodegenerative disorder that affects movement and is characterized by the loss of dopaminergic neurons in the nigrostriatal region. Although the clinical and pathological features of PD are complex, recent studies have indicated that microglial NADPH oxidase play a key role in its pathology. A little information is available regarding the role of apocyanin, an NADPH oxidase inhibitor, in ameliorating α-synuclein aggregation and neurobehavioral consequences of PD...
January 1, 2016: Behavioural Brain Research
https://www.readbyqxmd.com/read/26363495/depressive-like-phenotype-induced-by-aav-mediated-overexpression-of-human-%C3%AE-synuclein-in-midbrain-dopaminergic-neurons
#19
D Caudal, A Alvarsson, A Björklund, P Svenningsson
Parkinson's disease (PD) is a neurodegenerative disorder characterized by a progressive loss of nigral dopaminergic neurons and by the presence of aggregates containing α-synuclein called Lewy bodies. Viral vector-induced overexpression of α-synuclein in dopaminergic neurons represents a model of PD which recapitulates disease progression better than commonly used neurotoxin models. Previous studies using this model have reported motor and cognitive impairments, whereas depression, mood and anxiety phenotypes are less described...
November 2015: Experimental Neurology
https://www.readbyqxmd.com/read/26363201/differential-sensitivity-of-immature-and-mature-ventral-mesencephalic-neurons-to-rotenone-induced-neurotoxicity-in-vitro
#20
V Satish Bollimpelli, Anand K Kondapi
Rotenone induced neuronal toxicity in ventral mesencephalic (VM) dopaminergic (DA) neurons in culture is widely accepted as an important model for the investigation of Parkinson's disease (PD). However, little is known about developmental stage dependent toxic effects of rotenone on VM neurons in vitro. The objective of present study is to investigate the effect of rotenone on developing VM neurons at immature versus mature stages. Primary VM neurons were cultured in the absence of glial cells. Exposure of VM neurons to rotenone for 2 days induced cell death in both immature and mature neurons in a concentration-dependent manner, but to a greater extent in mature neurons...
December 25, 2015: Toxicology in Vitro: An International Journal Published in Association with BIBRA
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