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parkinson's disease and autophagy

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https://www.readbyqxmd.com/read/29456132/csf-lamp2-concentrations-are-decreased-in-female-parkinson-s-disease-patients-with-lrrk2-mutations
#1
Andrea C Klaver, Mary P Coffey, Jan O Aasly, David A Loeffler
Lysosome-associated membrane glycoprotein 2 (lamp2) plays critical roles in chaperone-mediated autophagy (CMA) and macroautophagy. Its isoform lamp2a is decreased in Parkinson's disease (PD) substantia nigra. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most known common cause of late-onset PD; although LRRK2 is thought to regulate macroautophagy, the influence of LRRK2 mutations on lamp2 concentrations in the CNS is unknown. To examine this issue we compared lamp2 levels in cerebrospinal fluid (CSF) between sporadic PD (sPD) patients (n = 31), LRRK2 PD patients (n = 20), and healthy control subjects with or without LRRK2 mutations (LRRK2 CTL = 30, CTL = 27)...
March 15, 2018: Brain Research
https://www.readbyqxmd.com/read/29451215/effect-of-moxibustion-on-mtor-mediated-autophagy-in-rotenone-induced-parkinson-s-disease-model-rats
#2
Shu-Ju Wang, Qi Wang, Jun Ma, Pei-Hao Yu, Zhong-Ming Wang, Bin Wang
Defects in autophagy-mediated clearance of α-synuclein may be one of the key factors leading to progressive loss of dopaminergic neurons in the substantia nigra. Moxibustion therapy for Parkinson's disease has been shown to have a positive effect, but the underlying mechanism remains unknown. Based on this, we explored whether moxibustion could protect dopaminergic neurons by promoting autophagy mediated by mammalian target of rapamycin (mTOR), with subsequent elimination of α-syn. A Parkinson's disease model was induced in rats by subcutaneous injection of rotenone at the back of their necks, and they received moxibustion at Zusanli (ST36), Guanyuan (CV4) and Fengfu (GV16), for 10 minutes at every point, once per day, for 14 consecutive days...
January 2018: Neural Regeneration Research
https://www.readbyqxmd.com/read/29439518/the-neuroprotective-effects-of-cinnamic-aldehyde-in-an-mptp-mouse-model-of-parkinson-s-disease
#3
Woom-Yee Bae, Jae-Sun Choi, Joo-Won Jeong
Cinnamic aldehyde (CA), a key flavor compound in cinnamon essential oil, has been identified as an anti-oxidant, anti-angiogenic, and anti-inflammatory material. Recently, the neuroprotective effects of CA have been reported in various neurodegenerative disorders, including Parkinson's disease (PD). In neurons, autophagy is tightly regulated, and consequently, the dysregulation of autophagy may induce neurodegenerative disorders. In the present study, we found that the selective dopaminergic neuronal death in the substantia nigra of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse models was prevented by CA...
February 12, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29434298/loss-of-autophagy-in-dopaminergic-neurons-causes-lewy-pathology-and-motor-dysfunction-in-aged-mice
#4
Shigeto Sato, Toshiki Uchihara, Takahiro Fukuda, Sachiko Noda, Hiromi Kondo, Shinji Saiki, Masaaki Komatsu, Yasuo Uchiyama, Keiji Tanaka, Nobutaka Hattori
Inactivation of constitutive autophagy results in the formation of cytoplasmic inclusions in neurons, but the relationship between impaired autophagy and Lewy bodies (LBs) as well as the in vivo process of formation remains unknown. Synuclein, a component of LBs, is the defining characteristic of Parkinson's disease (PD). Here, we characterize dopamine (DA) neuron-specific autophagy-deficient mice and provide in vivo evidence for LB formation. Synuclein deposition is preceded by p62 and resulted in the formation of inclusions containing synuclein and p62...
February 12, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29433359/piperlongumine-restores-the-balance-of-autophagy-and-apoptosis-by-increasing-bcl2-phosphorylation-in-rotenone-induced-parkinson-disease-models
#5
Jia Liu, Weijin Liu, Yongquan Lu, Hao Tian, Chunli Duan, Lingling Lu, Ge Gao, Xia Wu, Xiaomin Wang, Hui Yang
Parkinson disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease and is caused by genetics, environmental factors and aging, with few treatments currently available. Apoptosis and macroautophagy/autophagy play critical roles in PD pathogenesis; as such, modulating their balance is a potential treatment strategy. BCL2 (B cell leukemia/lymphoma 2) is a key molecule regulating this balance. Piperlongumine (PLG) is an alkaloid extracted from Piper longum L. that has anti-inflammatory and anticancer effects...
February 13, 2018: Autophagy
https://www.readbyqxmd.com/read/29429051/cilostazol-mediated-nurr1-and-autophagy-enhancement-neuroprotective-activity-in-rat-rotenone-pd-model
#6
Shireen A Hedya, Marwa M Safar, Ashraf K Bahgat
Nuclear receptor related 1 (Nurr1) orphan receptor has emerged as a promising contender in ameliorating Parkinson's disease; thus, finding a suitable activator of Nurr1 receptor is an attracting target for treating PD. Cilostazol, a phosphodiesterase-3 inhibitor, recently showed a favorable neuroprotective activity in multiple devastating central disorders, yet the possible antiparkinsonian activity of the drug has not been fully elucidated. Thus, the aim of this study is to explore the neuroprotective effect of cilostazol in rotenone-induced PD model in rats...
February 10, 2018: Molecular Neurobiology
https://www.readbyqxmd.com/read/29429047/the-small-gtpase-rac1-ced-10-is-essential-in-maintaining-dopaminergic-neuron-function-and-survival-against-%C3%AE-synuclein-induced-toxicity
#7
Hanna Kim, Carles Calatayud, Sangib Guha, Irene Fernández-Carasa, Laura Berkowitz, Iria Carballo-Carbajal, Mario Ezquerra, Rubén Fernández-Santiago, Pankaj Kapahi, Ángel Raya, Antonio Miranda-Vizuete, Jose Miguel Lizcano, Miquel Vila, Kim A Caldwell, Guy A Caldwell, Antonella Consiglio, Esther Dalfo
Parkinson's disease is associated with intracellular α-synuclein accumulation and ventral midbrain dopaminergic neuronal death in the Substantia Nigra of brain patients. The Rho GTPase pathway, mainly linking surface receptors to the organization of the actin and microtubule cytoskeletons, has been suggested to participate to Parkinson's disease pathogenesis. Nevertheless, its exact contribution remains obscure. To unveil the participation of the Rho GTPase family to the molecular pathogenesis of Parkinson's disease, we first used C elegans to demonstrate the role of the small GTPase RAC1 (ced-10 in the worm) in maintaining dopaminergic function and survival in the presence of alpha-synuclein...
February 10, 2018: Molecular Neurobiology
https://www.readbyqxmd.com/read/29422008/lysosomal-potassium-channels-potential-roles-in-lysosomal-function-and-neurodegenerative-diseases
#8
Xinghua Feng, Zhuangzhuang Zhao, Qian Li, Zhiyong Tan
The lysosome is a membrane-enclosed organelle widely found in every eukaryotic cell. It has been deemed as the stomach of the cells. Recent studies revealed that it also functions as an intracellular calcium store and is a platform for nutrient-dependent signal transduction. Similar with the plasma membrane, the lysosome membrane is furnished with various proteins, including pumps, ion channels and transporters. So far, two types of lysosomal potassium channels have been identified: large-conductance and Ca2+-activated potassium channel (BK) and TMEM175...
February 1, 2018: CNS & Neurological Disorders Drug Targets
https://www.readbyqxmd.com/read/29414102/drp-1-dependent-mitochondrial-fragmentation-and-protective-autophagy-in-dopaminergic-sh-sy5y-cells-overexpressing-alpha-synuclein
#9
Jimena Hebe Martinez, Agustina Alaimo, Roxana Mayra Gorojod, Soledad Porte Alcon, Federico Fuentes, Federico Coluccio Leskow, Mónica Lidia Kotler
Parkinson's disease is a neurodegenerative movement disorder caused by the loss of dopaminergic neurons from substantia nigra. It is characterized by the accumulation of aggregated α-synuclein as the major component of the Lewy bodies. Additional common features of this disease are the mitochondrial dysfunction and the activation/inhibition of autophagy both events associated to the intracellular accumulation of α-synuclein. The mechanism by which these events contribute to neural degeneration remains unknown...
January 27, 2018: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/29410282/osmotic-stress-induced-toxicity-exacerbates-parkinson-s-associated-effects-via-dysregulation-of-autophagy-in-transgenic-c-elegans-model
#10
Pooja Jadiya, Snober S Mir, Aamir Nazir
The accumulation of aggregate-prone proteins is a major representative of many neurological disorders, including Parkinson's disease (PD) wherein the cellular clearance mechanisms, such as the ubiquitin-proteasome and autophagy pathways are impaired. PD, known to be associated with multiple genetic and environmental factors, is characterized by the aggregation of α-synuclein protein and loss of dopaminergic neurons in midbrain. This disease is also associated with other cardiovascular ailments. Herein, we report our findings from studies on the effect of hyper and hypo-osmotic induced toxicity representing hyper and hypotensive condition as an extrinsic epigenetic factor towards modulation of Parkinsonism, using a genetic model Caenorhabditis elegans (C...
February 2, 2018: Cellular Signalling
https://www.readbyqxmd.com/read/29408515/andrographolide-a-diterpene-lactone-from-andrographis-paniculata-and-its-therapeutic-promises-in-cancer
#11
Muhammad Torequl Islam, Eunüs S Ali, Shaikh Jamal Uddin, Md Amirul Islam, Subrata Shaw, Ishaq N Khan, Seyed Soheil Saeedi Saravi, Saheem Ahmad, Shahnawaz Rehman, Vijai Kumar Gupta, Mihnea-Alexandru Găman, Amelia Maria Gaman, Santosh Yele, Asish Kumar Das, João Marcelo de Castro E Sousa, Sandra Maria Mendes de Moura Dantas, Hercília Maria Lins Rolim, Ana Amélia de Carvalho Melo-Cavalcante, Mohammad S Mubarak, Nagendra Sastry Yarla, Jamil A Shilpi, Siddhartha Kumar Mishra, Atanas G Atanasov, Mohammad Amjad Kamal
The diterpene lactone andrographolide, isolated from Andrographis paniculata, has been proven to possess several important protective biological activities, including antioxidant, anti-inflammatory, immunomodulatory, antiseptic, antimicrobial, cytotoxic, hypolipidemic, cardioprotective, hepatoprotective, and neuroprotective effects. In addition, it has been reported to play a therapeutic role in the treatment of major human diseases, such as Parkinson's disease, rheumatoid arthritis, and colitis. This systematic review aims to highlight andrographolide as a promising agent in cancer treatment...
February 2, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29400127/glucocerebrosidase-and-parkinson-disease-molecular-clinical-and-therapeutic-implications
#12
Roberta Balestrino, Anthony H V Schapira
Parkinson disease (PD) is a complex neurodegenerative disease characterised by multiple motor and non-motor symptoms. In the last 20 years, more than 20 genes have been identified as causes of parkinsonism. Following the observation of higher risk of PD in patients affected by Gaucher disease, a lysosomal disorder caused by mutations in the glucocerebrosidase (GBA) gene, it was discovered that mutations in this gene constitute the single largest risk factor for development of idiopathic PD. Patients with PD and GBA mutations are clinically indistinguishable from patients with idiopathic PD, although some characteristics emerge depending on the specific mutation, such as slightly earlier onset...
February 1, 2018: Neuroscientist: a Review Journal Bringing Neurobiology, Neurology and Psychiatry
https://www.readbyqxmd.com/read/29385658/the-role-of-glucocerebrosidase-in-parkinson-disease-pathogenesis
#13
Matthew E Gegg, Anthony H V Schapira
GBA encodes the lysosomal enzyme glucocerebrosidase (GCase), an enzyme involved in sphingolipid metabolism. Mutations in the GBA gene are numerically the most important risk factor for developing Parkinson disease (PD) accounting for at least 5% of all PD cases. Furthermore, loss of GCase activity is found in sporadic PD brains. Lysosomal dysfunction is thought to play a principal role in PD pathogenesis and in particular its effect on the metabolism of α-synuclein. A hallmark of PD is the presence intraneuronal protein inclusions called Lewy bodies, which are composed mainly of α-synuclein...
January 31, 2018: FEBS Journal
https://www.readbyqxmd.com/read/29383690/glia-maturation-factor-dependent-inhibition-of-mitochondrial-pgc-1%C3%AE-triggers-oxidative-stress-mediated-apoptosis-in-n27-rat-dopaminergic-neuronal-cells
#14
Govindhasamy Pushpavathi Selvakumar, Shankar S Iyer, Duraisamy Kempuraj, Murugesan Raju, Ramasamy Thangavel, Daniyal Saeed, Mohammad Ejaz Ahmed, Harris Zahoor, Sudhanshu P Raikwar, Smita Zaheer, Asgar Zaheer
Parkinson's disease (PD) is a progressive neurodegenerative disease affecting over five million individuals worldwide. The exact molecular events underlying PD pathogenesis are still not clearly known. Glia maturation factor (GMF), a neuroinflammatory protein in the brain plays an important role in the pathogenesis of PD. Mitochondrial dysfunctions and oxidative stress trigger apoptosis leading to dopaminergic neuronal degeneration in PD. Peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α or PPARGC-α) acts as a transcriptional co-regulator of mitochondrial biogenesis and energy metabolism by controlling oxidative phosphorylation, antioxidant activity, and autophagy...
January 30, 2018: Molecular Neurobiology
https://www.readbyqxmd.com/read/29368986/cholesterol-and-multilamellar-bodies-lyosomal-dysfunction-in-gba-parkinson-disease
#15
Patricia García-Sanz, Lorena Orgaz, José M Fuentes, Carlos Vicario, Rosario Moratalla
Lipid and cholesterol metabolism might play a role in the pathogenesis of Parkinson disease (PD). However, the association between cholesterol and PD is not clearly established. Cholesterol accumulation is closely related to the expression of multilamellar bodies (MLBs). Also, cholesterol controls autophagosome transport. Thus, impaired cholesterol and autophagosome trafficking might lead to robust autophagic vacuole accumulation. Our recent work provides the first evidence that the presence of the N370S GBA/GBA1 mutation produces an accumulation of cholesterol, which alters autophagy-lysosome function with the appearance of MLBs, rendering the cell more vulnerable and sensitive to apoptosis...
January 25, 2018: Autophagy
https://www.readbyqxmd.com/read/29367610/removal-of-prolyl-oligopeptidase-reduces-alpha-synuclein-toxicity-in-cells-and-in-vivo
#16
Reinis Svarcbahs, Ulrika H Julku, Susanna Norrbacka, Timo T Myöhänen
Prolyl oligopeptidase (PREP) inhibition by small-molecule inhibitors can reduce alpha-synuclein (aSyn) aggregation, a key player in Parkinson's disease pathology. However, the significance of PREP protein for aSyn aggregation and toxicity is not known. We studied this in vivo by using PREP knock-out mice with viral vector injections of aSyn and PREP. Animal behavior was studied by locomotor activity and cylinder tests, microdialysis and HPLC were used to analyze dopamine levels, and different aSyn forms and loss of dopaminergic neurons were studied by immunostainings...
January 24, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29362387/effects-of-ambroxol-on-the-autophagy-lysosome-pathway-and-mitochondria-in-primary-cortical-neurons
#17
J Magalhaes, M E Gegg, A Migdalska-Richards, A H Schapira
Glucocerebrosidase (GBA1) mutations are the major genetic risk factor for Parkinson's Disease (PD). The pathogenic mechanism is still unclear, but alterations in lysosomal-autophagy processes are implicated due to reduction of mutated glucocerebrosidase (GCase) in lysosomes. Wild-type GCase activity is also decreased in sporadic PD brains. Small molecule chaperones that increase lysosomal GCase activity have potential to be disease-modifying therapies for GBA1-associated and sporadic PD. Therefore we have used mouse cortical neurons to explore the effects of the chaperone ambroxol...
January 23, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29361800/heat-shock-proteins-and-autophagy-pathways-in-neuroprotection-from-molecular-bases-to-pharmacological-interventions
#18
REVIEW
Botond Penke, Ferenc Bogár, Tim Crul, Miklós Sántha, Melinda E Tóth, László Vígh
Neurodegenerative diseases (NDDs) such as Alzheimer's disease, Parkinson's disease and Huntington's disease (HD), amyotrophic lateral sclerosis, and prion diseases are all characterized by the accumulation of protein aggregates (amyloids) into inclusions and/or plaques. The ubiquitous presence of amyloids in NDDs suggests the involvement of disturbed protein homeostasis (proteostasis) in the underlying pathomechanisms. This review summarizes specific mechanisms that maintain proteostasis, including molecular chaperons, the ubiquitin-proteasome system (UPS), endoplasmic reticulum associated degradation (ERAD), and different autophagic pathways (chaperon mediated-, micro-, and macro-autophagy)...
January 22, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29360040/endosomal-rab-cycles-regulate-parkin-mediated-mitophagy
#19
Koji Yamano, Chunxin Wang, Shireen A Sarraf, Christian Münch, Reika Kikuchi, Nobuo N Noda, Yohei Hizukuri, Masato T Kanemaki, Wade Harper, Keiji Tanaka, Noriyuki Matsuda, Richard J Youle
Damaged mitochondria are selectively eliminated by mitophagy. Parkin and PINK1, gene products mutated in familial Parkinson's disease, play essential roles in mitophagy through ubiquitination of mitochondria. Cargo ubiquitination by E3 ubiquitin ligase Parkin is important to trigger selective autophagy. Although autophagy receptors recruit LC3-labeled autophagic membranes onto damaged mitochondria, how other essential autophagy units such as ATG9A-integrated vesicles are recruited remains unclear. Here, using mammalian cultured cells, we demonstrate that RABGEF1, the upstream factor of the endosomal Rab GTPase cascade, is recruited to damaged mitochondria via ubiquitin binding downstream of Parkin...
January 23, 2018: ELife
https://www.readbyqxmd.com/read/29358684/building-and-decoding-ubiquitin-chains-for-mitophagy
#20
REVIEW
J Wade Harper, Alban Ordureau, Jin-Mi Heo
Mitochondria produce energy in the form of ATP via oxidative phosphorylation. As defects in oxidative phosphorylation can generate harmful reactive oxygen species, it is important that damaged mitochondria are efficiently removed via a selective form of autophagy known as mitophagy. Owing to a combination of cell biological, structural and proteomic approaches, we are beginning to understand the mechanisms by which ubiquitin-dependent signals mark damaged mitochondria for mitophagy. This Review discusses the biochemical steps and regulatory mechanisms that promote the conjugation of ubiquitin to damaged mitochondria via the PTEN-induced putative kinase 1 (PINK1) and the E3 ubiquitin-protein ligase parkin and how ubiquitin chains promote autophagosomal capture...
January 23, 2018: Nature Reviews. Molecular Cell Biology
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