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parkinson's disease and endoplasmic reticulum stress

Haiying Shen, Kiyoon Kim, Yoojung Oh, Kyung Sik Yoon, Hyung Hwan Baik, Sung Soo Kim, Joohun Ha, Insug Kang, Wonchae Choe
β-N-methylamino-L-alanine (BMAA) is a neurotoxin that is closely associated with the incidence of amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease. In cultured neuronal cells, BMAA notably induces the upregulation of endoplasmic reticulum (ER) chaperons and activates the unfolded protein response (UPR) receptor pathways of protein kinase RNA‑like endoplasmic reticulum kinase, inositol‑requiring kinase 1 and transcription factor 6. The ER stress‑specific protein CCAAT/‑enhancer‑binding protein homologous protein (CHOP) affords pro‑apoptotic responses that cause mitochondrial damage and caspase activation...
October 5, 2016: Molecular Medicine Reports
Shaoxiao Wang, Siyuan Zhang, Chuan Xu, Addie Barron, Floyd Galiano, Dhaval Patel, Yong Joo Lee, Guy A Caldwell, Kim A Caldwell, Stephan N Witt
We have been investigating the role that phosphatidylethanolamine (PE) and phosphatidylcholine (PC) content plays in modulating the solubility of the Parkinson's disease protein alpha-synuclein (α-syn) using Saccharomyces cerevisiae and Caenorhabditis elegans. One enzyme that synthesizes PE is the conserved enzyme phosphatidylserine decarboxylase (Psd1/yeast; PSD-1/worms), which is lodged in the inner mitochondrial membrane. We previously found that decreasing the level of PE due to knockdown of Psd1/psd-1 affects the homeostasis of α-syn in vivo...
2016: PloS One
M Rodríguez-Arribas, S M S Yakhine-Diop, J M Bravo-San Pedro, P Gómez-Suaga, R Gómez-Sánchez, G Martínez-Chacón, J M Fuentes, R A González-Polo, M Niso-Santano
Mitochondria-associated membranes (MAMs) are structures that regulate physiological functions between endoplasmic reticulum (ER) and mitochondria in order to maintain calcium signaling and mitochondrial biogenesis. Several proteins located in MAMs, including those encoded by PARK genes and some of neurodegeneration-related proteins (huntingtin, presenilin, etc.), ensure this regulation. In this regard, MAM alteration is associated with neurodegenerative diseases such as Parkinson's (PD), Alzheimer's (AD), and Huntington's diseases (HD) and contributes to the appearance of the pathogenesis features, i...
October 6, 2016: Molecular Neurobiology
Valentín Cóppola-Segovia, Clarissa Cavarsan, Flavia G Maia, Anete C Ferraz, Lia S Nakao, Marcelo Ms Lima, Silvio M Zanata
Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive death of dopaminergic neurons of the substantia nigra pars compacta (SNpc), leading to the major clinical abnormalities that characterize this disease. Although PD's etiology is unknown, α-synuclein aggregation plays a pivotal role in PD pathogenesis, which could be associated to some pathological processes such as oxidative stress, endoplasmic reticulum (ER) stress, impaired protein degradation, and mitochondrial dysfunction...
September 22, 2016: Molecular Neurobiology
Parijat Kabiraj, Jose Eduardo Marin, Armando Varela-Ramirez, Mahesh Narayan
Amyloid beta (Aβ) aggregation is generally associated with Alzheimer's onset. Here, we demonstrate that incubation of dopaminergic SH-SY5Y cells with an Aβ peptide fragment (an 11-mer composed of residues 25-35; Aβ (25-35)) results in elevated intracellular nitrosative stress and induces chemical mutation of protein disulfide isomerase (PDI), an endoplasmic reticulum-resident oxidoreductase chaperone. Furthermore, Aβ (25-35) provokes aggregation of both the minor and major biomarkers of Parkinson's disease, namely, synphilin-1 and α-synuclein, respectively...
October 3, 2016: ACS Chemical Neuroscience
Zheng Mou, Yu-He Yuan, Yu-Xia Lou, Yang Heng, Ju-Yang Huang, Cong-Yuan Xia, Yan Gao, Cheng-Gen Zhu, Shi-Feng Chu, Piao Luo, Jian-Gong Shi, Nai-Hong Chen
AIM: Accumulation of α-synuclein (α-syn) in the brain is a characteristic of Parkinson's disease (PD). In this study, we investigated whether treatment with tunicamycin, an endoplasmic reticulum (ER) stress inducer, led to the accumulation of α-syn in PC12 cells, and where α-syn protein was accumulated, and, finally, whether bibenzyl compound 20c, a novel compound isolated from Gastrodia elata (Tian ma), could alleviate the accumulation of α-syn and ER stress activation in tunicamycin-treated PC12 cells...
September 12, 2016: Acta Pharmacologica Sinica
Carmen Avagliano, Roberto Russo, Carmen De Caro, Claudia Cristiano, Giovanna La Rana, Giuseppe Piegari, Orlando Paciello, Rita Citraro, Emilio Russo, Giovambattista De Sarro, Rosaria Meli, Giuseppina Mattace Raso, Antonio Calignano
Several pathogenetic factors have been involved in the onset and progression of Parkinson's disease (PD), including inflammation, oxidative stress, unfolded protein accumulation, and apoptosis. Palmitoylethanolamide (PEA), an endogenous N-acylethanolamine, has been shown to be a neuroprotective and anti-inflammatory molecule, acting as a peroxisome proliferator activated receptor (PPAR)-α agonist. In this study we investigated the effects of PEA on behavioral alterations and the underlying pathogenic mechanisms in the 6-hydroxydopamine (6-OHDA)-induced model of PD in male mice...
September 8, 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Ana Sofia Carvalho, Manuel S Rodríguez, Rune Matthiesen
Automatic analysis of increasingly growing literature repositories including data integration to other databases is a powerful tool to propose hypothesis that can be used to plan experiments to validate or disprove the hypothesis. Furthermore, it provides means to evaluate the redundancy of research line in comparison to the published literature. This is potentially beneficial for those developing research in a specific disease which are interested in exploring a particular pathway or set of genes/proteins...
2016: Methods in Molecular Biology
Dexiang Liu, Zunji Ke, Jia Luo
Thiamine (vitamin B1) is an essential nutrient and indispensable for normal growth and development of the organism due to its multilateral participation in key biochemical and physiological processes. Humans must obtain thiamine from their diet since it is synthesized only in bacteria, fungi, and plants. Thiamine deficiency (TD) can result from inadequate intake, increased requirement, excessive deletion, and chronic alcohol consumption. TD affects multiple organ systems, including the cardiovascular, muscular, gastrointestinal, and central and peripheral nervous systems...
September 5, 2016: Molecular Neurobiology
Yoojung Oh, Kwon Jeong, Kiyoon Kim, Young-Seok Lee, Suyun Jeong, Sung Soo Kim, Kyung-Sik Yoon, Joohun Ha, Insug Kang, Wonchae Choe
Parkinson's disease (PD) is the second most common neurodegenerative disorder of aging. PD involves a progressive loss of dopaminergic neurons in the substantia nigra pars compacta. 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyidine (MPTP) and its toxic metabolite 1-methyl-4-phenylpyridinium ion (MPP+) inhibit the complex I of the mitochondrial electron transport chain, and have been widely used to construct PD models. Cyclophilin B (CypB) is an endoplasmic reticulum protein that binds to cyclosporine A as a cyclophilin family member...
September 23, 2016: Biochemical and Biophysical Research Communications
Alvaro Sanchez-Martinez, Michelle Beavan, Matthew E Gegg, Kai-Yin Chau, Alexander J Whitworth, Anthony H V Schapira
GBA gene mutations are the greatest cause of Parkinson disease (PD). GBA encodes the lysosomal enzyme glucocerebrosidase (GCase) but the mechanisms by which loss of GCase contributes to PD remain unclear. Inhibition of autophagy and the generation of endoplasmic reticulum (ER) stress are both implicated. Mutant GCase can unfold in the ER and be degraded via the unfolded protein response, activating ER stress and reducing lysosomal GCase. Small molecule chaperones that cross the blood brain barrier help mutant GCase refold and traffic correctly to lysosomes are putative treatments for PD...
2016: Scientific Reports
Euteum Park, Hong Sung Chun
Dieldrin, an organochlorine pesticide still used in several developing countries, has been proposed as a risk factor for Parkinson's disease. Quercetin is one of the potent bioactive flavonoids present in numerous plants. In this study, we investigated the protective effects of quercetin on neurotoxicity induced by dieldrin in cultured dopaminergic SN4741 cells. Our initial experiments showed that quercetin (10-40 μM) dose dependently prevented dieldrin (20 μM)-induced cytotoxicity in SN4741 cells. Pretreatment for 1 h with quercetin before dieldrin application could significantly suppress dieldrin-induced apoptotic characteristics, including nuclear condensation, DNA fragmentation, and caspase-3/7 activation...
October 19, 2016: Neuroreport
Pingtao Cai, Jingjing Ye, Jingjing Zhu, Dan Liu, Daqing Chen, Xiaojie Wei, Noah R Johnson, Zhouguang Wang, Hongyu Zhang, Guodong Cao, Jian Xiao, Junming Ye, Li Lin
Parkinson's disease (PD) is a progressive neurodegenerative disorder with complicated pathophysiologic mechanisms. Endoplasmic reticulum (ER) stress appears to play a critical role in the progression of PD. We demonstrated that basic fibroblast growth factor (bFGF), as a neurotropic factor, inhibited ER stress-induced neuronal cell apoptosis and that 6-hydroxydopamine (6-OHDA)-induced ER stress was involved in the progression of PD in rats. bFGF administration improved motor function recovery, increased tyrosine hydroxylase (TH)-positive neuron survival, and upregulated the levels of neurotransmitters in PD rats...
August 2016: Aging and Disease
Faten Taram, Aimee N Winter, Daniel A Linseman
While the number of patients diagnosed with neurodegenerative disorders like Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease is increasing, there are currently no effective treatments that significantly limit the neuronal cell death underlying these diseases. Chlorogenic acid (CGA), a polyphenolic compound found in high concentration in coffee, is known to possess antioxidant and free radical scavenging activity. In this study, we investigated the neuroprotective effects of CGA and its major metabolites in primary cultures of rat cerebellar granule neurons...
October 1, 2016: Brain Research
Navya Lakkappa, Praveen T Krishnamurthy, Bruce D Hammock, D Velmurugan, M M Srinivas Bharath
Parkinson's disease (PD) is a multifactorial neurodegenerative disease involving oxidative stress, neuroinflammation and apoptosis. Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites and they play a role in cytoprotection by modulating various cell signaling pathways. This cytoprotective role of EETs are well established in cerebral stroke, cardiac failure, and hypertension, and it is due to their ability to attenuate oxidative stress, endoplasmic reticulum stress, inflammation, caspase activation and apoptosis...
August 2016: Medical Hypotheses
Sumit Sarkar, James Raymick, Syed Imam
Parkinsonism is a progressive motor disease that affects 1.5 million Americans and is the second most common neurodegenerative disease after Alzheimer's. Typical neuropathological features of Parkinson's disease (PD) include degeneration of dopaminergic neurons located in the pars compacta of the substantia nigra that project to the striatum (nigro-striatal pathway) and depositions of cytoplasmic fibrillary inclusions (Lewy bodies) which contain ubiquitin and α-synuclein. The cardinal motor signs of PD are tremors, rigidity, slow movement (bradykinesia), poor balance, and difficulty in walking (Parkinsonian gait)...
2016: International Journal of Molecular Sciences
I Celardo, A C Costa, S Lehmann, C Jones, N Wood, N E Mencacci, G R Mallucci, S H Y Loh, L M Martins
Mutations in PINK1 and PARKIN cause early-onset Parkinson's disease (PD), thought to be due to mitochondrial toxicity. Here, we show that in Drosophila pink1 and parkin mutants, defective mitochondria also give rise to endoplasmic reticulum (ER) stress signalling, specifically to the activation of the protein kinase R-like endoplasmic reticulum kinase (PERK) branch of the unfolded protein response (UPR). We show that enhanced ER stress signalling in pink1 and parkin mutants is mediated by mitofusin bridges, which occur between defective mitochondria and the ER...
2016: Cell Death & Disease
Nivanthika K Wimalasena, Viet Q Le, Kandatege Wimalasena, Stuart L Schreiber, Rakesh Karmacharya
We carried out a gene expression-based in silico screen in order to identify small molecules with gene-expression profiles that are anticorrelated with a gene-expression profile for Parkinson's disease (PD). We identified the cyclin-dependent kinase 2/5 (CDK2/5) inhibitor GW8510 as our most significant hit and characterized its effects in rodent MN9D cells and in human neuronal cells derived from induced pluripotent stem cells. GW8510 demonstrated neuroprotective ability in MN9D cells in the presence of 1-methyl-4-phenylpyridium (MPP(+)), a widely used neurotoxin model for Parkinson's disease...
July 20, 2016: ACS Chemical Neuroscience
Hemat E El-Horany, Rania N Abd El-Latif, Maha M ElBatsh, Marwa N Emam
Autophagy is necessary for neuronal homeostasis and its dysfunction has been implicated in Parkinson's disease (PD) as it can exacerbate endoplasmic reticulum (ER) stress and ER stress-induced apoptosis. Quercetin is a flavonoid known for its neuroprotective and antioxidant effects. The present study investigated the protective, autophagy-modulating effects of quercetin in the rotenone rat model of PD. Rotenone was intraperitoneally injected at dose of 2 ml/kg/day for 4 weeks. Simultaneous intraperitoneal injection of quercetin was given at a dose of 50 mg/kg/day also for 4 weeks...
July 2016: Journal of Biochemical and Molecular Toxicology
Masayuki Kaneko
Studies on endoplasmic reticulum (ER)-associated degradation (ERAD), in which unfolded proteins accumulated in the ER are selectively transported to the cytosol for degradation by the ubiquitin-proteasome system, have been focused on molecular mechanisms in yeast. In human, disruption of the ER quality control system causes various diseases, such as neurodegenerative disease, lifestyle disease, and cancer. However, there are many ERAD genes with unknown physiological and pathological functions. We identified the novel ubiquitin ligase HRD1 involved in ERAD...
2016: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
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