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parkinson's disease and mitochondria

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https://www.readbyqxmd.com/read/29137980/interaction-of-alpha-synuclein-with-cytogaligin-a-protein-encoded-by-the-proapoptotic-gene-galig
#1
Saïd El Haddad, Amandine Serrano, Thierry Normand, Chloé Robin, Martine Dubois, Fabienne Brule-Morabito, Lucile Mollet, Stéphane Charpentier, Alain Legrand
GALIG, an internal gene to the human galectin-3 gene, encodes two distinct proteins, Mitogaligin and Cytogaligin through translation of a unique mRNA in two overlapping alternative reading frames. When overexpressed GALIG induces apoptosis. In cultured cells, Mitogaligin destabilizes mitochondria membranes through interaction with cardiolipin. Little is known regarding the role of Cytogaligin. This protein displays multiple subcellular localizations; cytosol, nucleus, and mitochondria. We illustrate here that Cytogaligin is also secreted in the extracellular medium...
November 11, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29123128/pink1-mediated-phosphorylation-of-letm1-regulates-mitochondrial-calcium-transport-and-protects-neurons-against-mitochondrial-stress
#2
En Huang, Dianbo Qu, Tianwen Huang, Nicoletta Rizzi, Wassamon Boonying, Dorothy Krolak, Paolo Ciana, John Woulfe, Christine Klein, Ruth S Slack, Daniel Figeys, David S Park
Mutations in PTEN-induced kinase 1 (PINK1) result in a recessive familial form of Parkinson's disease (PD). PINK1 loss is associated with mitochondrial Ca(2+) mishandling, mitochondrial dysfunction, as well as increased neuronal vulnerability. Here we demonstrate that PINK1 directly interacts with and phosphorylates LETM1 at Thr192 in vitro. Phosphorylated LETM1 or the phospho-mimetic LETM1-T192E increase calcium release in artificial liposomes and facilitates calcium transport in intact mitochondria. Expression of LETM1-T192E but not LETM1-wild type (WT) rescues mitochondrial calcium mishandling in PINK1-deficient neurons...
November 9, 2017: Nature Communications
https://www.readbyqxmd.com/read/29121267/loss-of-chchd10-chchd2-complexes-required-for-respiration-underlies-the-pathogenicity-of-a-chchd10-mutation-in-als
#3
Isabella R Straub, Alexander Janer, Woranontee Weraarpachai, Lorne Zinman, Janice Robertson, Ekaterina Rogaeva, Eric A Shoubridge
CHCHD10 and its paralogue CHCHD2 belong to a family of twin CX9C motif proteins, most of which localize to the intermembrane space of mitochondria. Dominant mutations in CHCHD10 cause amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD), and mutations in CHCHD2 have been associated with Parkinson's disease, but the function of these proteins remains unknown. Here we show that the p.R15L CHCHD10 variant in ALS patient fibroblasts destabilizes the protein, leading to a defect in the assembly of complex I, impaired cellular respiration, mitochondrial hyperfusion, an increase in the steady-state level of CHCHD2, and a severe proliferation defect on galactose, a substrate that forces cells to synthesize virtually all of their ATP aerobically...
November 7, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/29097687/genome-scale-single-cell-mechanical-phenotyping-reveals-disease-related-genes-involved-in-mitotic-rounding
#4
Yusuke Toyoda, Cedric J Cattin, Martin P Stewart, Ina Poser, Mirko Theis, Teymuras V Kurzchalia, Frank Buchholz, Anthony A Hyman, Daniel J Müller
To divide, most animal cells drastically change shape and round up against extracellular confinement. Mitotic cells facilitate this process by generating intracellular pressure, which the contractile actomyosin cortex directs into shape. Here, we introduce a genome-scale microcantilever- and RNAi-based approach to phenotype the contribution of > 1000 genes to the rounding of single mitotic cells against confinement. Our screen analyzes the rounding force, pressure and volume of mitotic cells and localizes selected proteins...
November 2, 2017: Nature Communications
https://www.readbyqxmd.com/read/29089438/human-astrocytes-transfer-aggregated-alpha-synuclein-via-tunneling-nanotubes
#5
Jinar Rostami, Staffan Holmqvist, Veronica Lindström, Jessica Sigvardson, Gunilla T Westermark, Martin Ingelsson, Joakim Bergström, Laurent Roybon, Anna Erlandsson
Many lines of evidence suggest that the Parkinson's disease (PD) related protein alpha-synuclein (α-SYN) can propagate from cell-to-cell in a prion-like manner. However, the cellular mechanisms behind the spreading remain elusive. Here, we show that human astrocytes, derived from embryonic stem cells, actively transfer aggregated α-SYN to nearby astrocytes via direct contact and tunneling nanotubes (TNTs). Failure in the astrocytes' lysosomal digestion of excess α-SYN oligomers, results in α-SYN deposits in the trans-Golgi network followed by endoplasmic reticulum swelling and mitochondrial disturbances...
October 31, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29079356/parkin-overexpression-in-human-mesenchymal-stromal-cells-from-wharton-s-jelly-suppresses-6-hydroxydopamine-induced-apoptosis-potential-therapeutic-strategy-in-parkinson-s-disease
#6
A R Bonilla-Porras, A Arevalo-Arbelaez, J F Alzate-Restrepo, C Velez-Pardo, M Jimenez-Del-Rio
BACKGROUND AIMS: Stem cell transplantation is an excellent option for regenerative or replacement therapy. However, deleterious microenvironmental and endogenous factors (e.g., oxidative stress) compromise ongoing graft survival and longevity. Therefore, (transient or stable) genetically modified cells may be reasonably thought to resist oxidative stress-induced damage. Genetic engineering of mesenchymal stromal cells (MSCs) obtained from Wharton's jelly tissue may offer some therapeutic potential...
October 24, 2017: Cytotherapy
https://www.readbyqxmd.com/read/29077060/oxidative-stress-mechanistic-insights-into-inherited-mitochondrial-disorders-and-parkinson-s-disease
#7
REVIEW
Mesfer Al Shahrani, Simon Heales, Iain Hargreaves, Michael Orford
Oxidative stress arises when cellular antioxidant defences become overwhelmed by a surplus generation of reactive oxygen species (ROS). Once this occurs, many cellular biomolecules such as DNA, lipids, and proteins become susceptible to free radical-induced oxidative damage, and this may consequently lead to cellular and ultimately tissue and organ dysfunction. Mitochondria, as well as being a source of ROS, are vulnerable to oxidative stress-induced damage with a number of key biomolecules being the target of oxidative damage by free radicals, including membrane phospholipids, respiratory chain complexes, proteins, and mitochondrial DNA (mt DNA)...
October 27, 2017: Journal of Clinical Medicine
https://www.readbyqxmd.com/read/29057315/mitochondrial-impairment-in-microglia-amplifies-nlrp3-inflammasome-proinflammatory-signaling-in-cell-culture-and-animal-models-of-parkinson-s-disease
#8
Souvarish Sarkar, Emir Malovic, Dilshan S Harishchandra, Shivani Ghaisas, Nikhil Panicker, Adhithiya Charli, Bharathi N Palanisamy, Dharmin Rokad, Huajun Jin, Vellareddy Anantharam, Arthi Kanthasamy, Anumantha G Kanthasamy
The NLRP3 inflammasome signaling pathway is a major contributor to the neuroinflammatory process in the central nervous system. Oxidative stress and mitochondrial dysfunction are key pathophysiological processes of many chronic neurodegenerative diseases, including Parkinson's disease (PD). However, the inter-relationship between mitochondrial defects and neuroinflammation is not well understood. In the present study, we show that impaired mitochondrial function can augment the NLRP3 inflammasome-driven proinflammatory cascade in microglia...
2017: NPJ Parkinson's Disease
https://www.readbyqxmd.com/read/29054108/increase-in-pro-apoptotic-activity-of-inhibitory-pas-domain-protein-via-phosphorylation-by-mk2
#9
Shuya Kasai, Mary Jane Elizabeth Richardson, Satoru Torii, Ken-Ichi Yasumoto, Hiroki Shima, Kazuhiko Igarashi, Ken Itoh, Kazuhiro Sogawa, Kazutaka Murayama
Inhibitory PAS domain protein (IPAS) is a bifunctional protein that downregulates hypoxic gene expression and exerts pro-apoptotic activity by preventing pro-survival activity of Bcl-xL and its related factors. Pro-apoptotic activity of IPAS is attenuated by the activation of the PINK1-Parkin pathway, and involved in neuronal degeneration in an experimental mouse model of Parkinson's disease. The current study shows that phosphorylation of IPAS at Ser184 by MAPK-activated protein kinase 2 (MK2 or MAPKAPK2) enhances the pro-apoptotic function of IPAS...
October 20, 2017: FEBS Journal
https://www.readbyqxmd.com/read/29046661/mitophagy-in-parkinson-s-disease-pathogenic-and-therapeutic-implications
#10
REVIEW
Fei Gao, Jia Yang, Dongdong Wang, Chao Li, Yi Fu, Huaishan Wang, Wei He, Jianmin Zhang
Neurons affected in Parkinson's disease (PD) experience mitochondrial dysfunction and bioenergetic deficits that occur early and promote the disease-related α-synucleinopathy. Emerging findings suggest that the autophagy-lysosome pathway, which removes damaged mitochondria (mitophagy), is also compromised in PD and results in the accumulation of dysfunctional mitochondria. Studies using genetic-modulated or toxin-induced animal and cellular models as well as postmortem human tissue indicate that impaired mitophagy might be a critical factor in the pathogenesis of synaptic dysfunction and the aggregation of misfolded proteins, which in turn impairs mitochondrial homeostasis...
2017: Frontiers in Neurology
https://www.readbyqxmd.com/read/29040870/parkin-absence-accelerates-microtubule-aging-in-dopaminergic-neurons
#11
Daniele Cartelli, Alida Amadeo, Alessandra Maria Calogero, Francesca Vittoria Marialuisa Casagrande, Carmelita De Gregorio, Mariarosa Gioria, Naoko Kuzumaki, Ilaria Costa, Jenny Sassone, Andrea Ciammola, Nobutaka Hattori, Hideyuki Okano, Stefano Goldwurm, Laurent Roybon, Gianni Pezzoli, Graziella Cappelletti
Loss-of-function caused by mutations in the parkin gene (PARK2) lead to early-onset familial Parkinson's disease. Recently, mechanistic studies proved the ability of parkin in regulating mitochondria homeostasis and microtubule (MT) stability. Looking at these systems during aging of PARK2 knockout mice, we found that loss of parkin induced an accelerated (over)acetylation of MT system both in dopaminergic neuron cell bodies and fibers, localized in the substantia nigra and corpus striatum, respectively. Interestingly, in PARK2 knockout mice, changes of MT stability preceded the alteration of mitochondria transport...
September 20, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/29038245/mitochondrial-calcium-dysregulation-contributes-to-dendrite-degeneration-mediated-by-pd-lbd-associated-lrrk2-mutants
#12
Manish Verma, Jason Callio, P Anthony Otero, Israel Sekler, Zachary P Wills, Charleen T Chu
Mutations in leucine-rich repeat kinase 2 (LRRK2) contribute to development of late-onset familial Parkinson's disease (PD), with clinical features of motor and cognitive dysfunction indistinguishable from sporadic PD. Calcium dysregulation plays an important role in PD pathogenesis, but the mechanisms of neurodegeneration remain unclear. Recent reports indicate enhanced excitatory neurotransmission in cortical neurons expressing mutant LRRK2, which occurs prior to the well-characterized phenotype of dendritic shortening...
October 16, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29030433/dysregulation-of-the-mitochondrial-unfolded-protein-response-induces-non-apoptotic-dopaminergic-neurodegeneration-in-c-elegans-models-of-parkinson-s-disease
#13
Bryan A Martinez, Daniel A Petersen, Anthony L Gaeta, Samuel P Stanley, Guy A Caldwell, Kim A Caldwell
Due to environmental insult or innate genetic deficiency, protein folding environments of the mitochondrial matrix are prone to dysregulation, prompting the activation of a specific organellar stress-response mechanism, the mitochondrial unfolded protein response (UPR(MT)). In Caenorhabditis elegans, mitochondrial damage leads to nuclear translocation of the ATFS-1 transcription factor to activate the UPR(MT) After short-term acute stress has been mitigated, the UPR(MT) is eventually suppressed to restore homeostasis to C...
November 15, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29022898/superoxide-drives-progression-of-parkin-pink1-dependent-mitophagy-following-translocation-of-parkin-to-mitochondria
#14
Bin Xiao, Xiao Deng, Grace G Y Lim, Shaoping Xie, Zhi Dong Zhou, Kah-Leong Lim, Eng-King Tan
Reactive oxygen species (ROS) and mitophagy are profoundly implicated in the pathogenesis of neurodegenerative diseases, such as Parkinson's disease (PD). Several studies have suggested that ROS are not involved in mitochondrial translocation of Parkin which primes mitochondria for autophagic elimination. However, whether ROS play a role in the execution of mitophagy is unknown. In the present study, we show that carbonyl cyanide m-chlorophenylhydrazone (CCCP) treatment induced both mitochondrial depolarization and generation of ROS that were needed for the mitophagy process...
October 12, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/29022502/pathophysiological-role-of-mitochondrial-potassium-channels-and-their-modulation-by-drugs
#15
Valentina Citi, Vincenzo Calderone, Alma Martelli, Maria Cristina Breschi, Lara Testai
Mitochondria play a central role in ATP-generating processes. Indeed, in mammalian tissues, up to 90% of ATP is generated by mitochondria through the process of oxidative phosphorylation; furthermore, mitochondria are involved in multiple signal transduction pathways. A rapidly expanding body of literature has confirmed that mitochondria play a pivotal role in apoptosis, cardio- and neuro-protection, and various neurodegenerative disorders, ranging from Parkinson's to Alzheimer's disease. It is evident that mitochondria are also the targets of multiple drugs; some of these are exactly designed to influence mitochondrial function, while others have primary targets in other cellular locations but may interact with mitochondria because of the presence of numerous targets on this organelle...
October 12, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29019159/alpha-lipoamide-ameliorates-motor-deficits-and-mitochondrial-dynamics-in-the-parkinson-s-disease-model-induced-by-6-hydroxydopamine
#16
Bo Zhou, Min Wen, Xin Lin, Yun-Hua Chen, Yun Gou, Yong Li, Yi Zhang, Hong-Wei Li, Lei Tang
The precise mechanisms underlying neuronal injury in Parkinson's disease (PD) are not yet fully elucidated; however, evidence from the in vitro and in vivo PD models suggest that mitochondrial dysfunction may play a major role in PD pathogenesis. Alpha lipoamide, a neutral amide derivative of the lipoic acid, is a better cofactor for mitochondrial dehydrogenase with a stronger protective effect on mitochondria than lipoic acid. Identification of these protective effects of alpha lipoamide on mitochondria, together with the evidence that mitochondrial dysfunction plays a critical role in PD, we speculate that alpha lipoamide may exert a protective effect in PD by regulating the mitochondrial function...
October 10, 2017: Neurotoxicity Research
https://www.readbyqxmd.com/read/28990084/neuroprotective-effect-of-chondroitin-sulfate-on-sh%C3%A2-sy5y-cells-overexpressing-wild%C3%A2-type-or-a53t-mutant-%C3%AE-%C3%A2-synuclein
#17
Chuanxia Ju, Jianjun Gao, Lin Hou, Lei Wang, Fang Zhang, Fusheng Sun, Tingting Zhang, Pingping Xu, Zhenyan Shi, Fang Hu, Congxiao Zhang
Accumulation of α‑synuclein (α‑SYN) is a common pathology for Parkinson's disease (PD). There is abundant evidence that the toxic‑gain‑of‑function of α‑SYN's is associated with aggregation and consequent effects. To assess the potential of chondroitin sulfate (CS) in this regard, the present study investigated its neuroprotective on SH‑SY5Y cells overexpressing wild‑type (WT) or A53T mutant α‑SYN. Cell viability was measured by MTT assay. Apoptosis, reactive oxygen species (ROS) and mitochondrial membrane potential were detected by flow cytometry...
December 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28986235/alpha-synuclein-epigenetics-mitochondria-metabolism-calcium-traffic-circadian-dysfunction-in-parkinson-s-disease-an-integrated-strategy-for-management
#18
REVIEW
Oliver T Phillipson
The motor deficits which characterise the sporadic form of Parkinson's disease arise from age-related loss of a subset of dopamine neurons in the substantia nigra. Although motor symptoms respond to dopamine replacement therapies, the underlying disease process remains. This review details some features of the progressive molecular pathology and proposes deployment of a combination of nutrients: R-lipoic acid, acetyl-l-carnitine, ubiquinol, melatonin (or receptor agonists) and vitamin D3, with the collective potential to slow progression of these features...
November 2017: Ageing Research Reviews
https://www.readbyqxmd.com/read/28986232/rifampicin-inhibits-rotenone-induced-microglial-inflammation-via-enhancement-of-autophagy
#19
Yanran Liang, Tianen Zhou, Ying Chen, Danyu Lin, Xiuna Jing, Sudan Peng, Dezhi Zheng, Zhifen Zeng, Ming Lei, Xia Wu, Kaixun Huang, Lianhong Yang, Songhua Xiao, Jun Liu, Enxiang Tao
Mitochondrial and autophagic dysfunction, as well as neuroinflammation, are associated with the pathophysiology of Parkinson's disease (PD). Rotenone, an inhibitor of mitochondrial complex I, has been associated as an environmental neurotoxin related to PD. Our previous studies reported that rifampicin inhibited microglia activation and production of proinflammatory mediators induced by rotenone, but the precise mechanism has not been completely elucidated. BV2 cells were pretreated for 2h with rifampicin followed by 0...
October 3, 2017: Neurotoxicology
https://www.readbyqxmd.com/read/28986095/modulation-of-mitochondrial-dynamics-by-treadmill-training-to-improve-gait-and-mitochondrial-deficiency-in-a-rat-model-of-parkinson-s-disease
#20
Chieh-Sen Chuang, Jui-Chih Chang, Fu-Chou Cheng, Ko-Hung Liu, Hong-Lin Su, Chin-San Liu
PURPOSE: Parkinson's disease (PD) is a progressive degenerative central nervous system disorder that particularly impairs motor function. As PD advances, gait disorders become more pronounced and are often difficult to treat with current pharmacological therapies. Physical activity improves both mobility in and the daily living activities of patients with PD. Mitochondrial alterations and oxidative stress contribute to PD progression. Therefore, the association between mitochondria and exercise in PD and the implicated regulation of mitochondrial proteins was explored in this study...
October 3, 2017: Life Sciences
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