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https://www.readbyqxmd.com/read/28894968/lysosomal-defects-in-atp13a2-and-gba-associated-familial-parkinson-s-disease
#1
Shigeto Sato, Yuanzhe Li, Nobutaka Hattori
Genes encoding lysosomal proteins, such as ATP13A2 and GBA, are associated with familial Parkinson's disease (PD). Heterozygous mutations in GBA are strongly associated with familial PD. ATP13A2, which encodes a lysosomal P-type ATPase, has been identified as the causative gene for Kufor-Rakeb syndrome. While lysosomal dysfunction due to these mutations exhibited early onset Parkinsonism, each animal model demonstrated different pathological mechanisms. Clinicogenetic and animal model studies recently identified several lysosomal alterations that play a role in the pathogenesis of PD...
September 11, 2017: Journal of Neural Transmission
https://www.readbyqxmd.com/read/28821231/novel-mutations-in-pank2-and-pla2g6-genes-in-patients-with-neurodegenerative-disorders-two-case-reports
#2
Hassan Dastsooz, Hamid Nemati, Mohammad Ali Farazi Fard, Majid Fardaei, Mohammad Ali Faghihi
BACKGROUND: Neurodegeneration with brain iron accumulation (NBIA) is a genetically heterogeneous group of disorders associated with progressive impairment of movement, vision, and cognition. The disease is initially diagnosed on the basis of changes in brain magnetic resonance imaging which indicate an abnormal brain iron accumulation in the basal ganglia. However, the diagnosis of specific types should be based on both clinical findings and molecular genetic testing for genes associated with different types of NBIA, including PANK2, PLA2G6, C19orf12, FA2H, ATP13A2, WDR45, COASY, FTL, CP, and DCAF17...
August 18, 2017: BMC Medical Genetics
https://www.readbyqxmd.com/read/28755477/thioredoxin-interacting-protein-induced-%C3%AE-synuclein-accumulation-via-inhibition-of-autophagic-flux-implications-for-parkinson-s-disease
#3
Cun-Jin Su, Yu Feng, Teng-Teng Liu, Xu Liu, Jun-Jie Bao, Ai-Ming Shi, Duan-Min Hu, Tong Liu, Yun-Li Yu
AIMS: Thioredoxin-interacting protein (TXNIP) is associated with activation of oxidative stress through inhibition of thioredoxin (Trx). However, some evidences point out that TXNIP acts as a scaffolding protein in signaling complex independent of cellular redox regulation. The autophagy-lysosomal pathway plays important roles in the clearance of misfolded proteins and dysfunctional organelles. Lysosomal dysfunction has been involved in several neurodegenerative disorders including Parkinson's disease (PD)...
September 2017: CNS Neuroscience & Therapeutics
https://www.readbyqxmd.com/read/28595912/the-effect-of-manganese-exposure-in-atp13a2-deficient-mice
#4
Sheila M Fleming, Nicholas A Santiago, Elizabeth J Mullin, Shanta Pamphile, Swagata Karkare, Andrew Lemkuhl, Osunde R Ekhator, Stephen C Linn, John G Holden, Diana S Aga, Jerome A Roth, Benjamin Liou, Ying Sun, Gary E Shull, Patrick J Schultheis
Loss of function mutations in the P5-ATPase ATP13A2 are associated with Kufor-Rakeb Syndrome and Neuronal Ceroid Lipofuscinosis. While the function of ATP13A2 is unclear, in vitro studies suggest it is a lysosomal protein that interacts with the metals manganese (Mn) and zinc and the presynaptic protein alpha-synuclein. Loss of ATP13A2 function in mice causes sensorimotor deficits, enhanced autofluorescent storage material, and accumulation of alpha-synuclein. The present study sought to determine the effect of Mn administration on these same outcomes in ATP13A2-deficient mice...
June 6, 2017: Neurotoxicology
https://www.readbyqxmd.com/read/28542792/on-the-complexity-of-clinical-and-molecular-bases-of-neurodegeneration-with-brain-iron-accumulation
#5
REVIEW
C Tello, A Darling, V Lupo, B Pérez-Dueñas, C Espinós
Neurodegeneration with brain iron accumulation (NBIA) is a group of inherited heterogeneous neurodegenerative rare disorders. These patients present with dystonia, spasticity, parkinsonism and neuropsychiatric disturbances, along with brain magnetic resonance imaging (MRI) evidence of iron accumulation. In sum, they are devastating disorders and to date, there is no specific treatment. Ten NBIA genes are accepted: PANK2, PLA2G6, C19orf12, COASY, FA2H, ATP13A2, WDR45, FTL, CP, and DCAF17; and nonetheless, a relevant percentage of patients remain without genetic diagnosis, suggesting that other novel NBIA genes remain to be discovered...
May 23, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28541025/structural-genomic-variations-and-parkinson-s-disease
#6
REVIEW
Sara Bandrés-Ciga, Clara Ruz, Francisco J Barrero, Francisco Escamilla-Sevilla, Javier Pelegrina, Francisco Vives, Raquel Duran
Parkinson's disease (PD) is the second most common neurodegenerative disease, whose prevalence is projected to be between 8.7 and 9.3 million by 2030. Until about 20 years ago, PD was considered to be the textbook example of a "non-genetic" disorder. Nowadays, PD is generally considered a multifactorial disorder that arises from the combination and complex interaction of genes and environmental factors. To date, a total of 7 genes including SNCA, LRRK2, PARK2, DJ-1, PINK 1, VPS35 and ATP13A2 have been seen to cause unequivocally Mendelian PD...
October 2017: Minerva Medica
https://www.readbyqxmd.com/read/28445716/trumping-neurodegeneration-targeting-common-pathways-regulated-by-autosomal-recessive-parkinson-s-disease-genes
#7
REVIEW
Laura Scott, Valina L Dawson, Ted M Dawson
Parkinson's disease (PD) is a neurodegenerative movement disorder characterized by the progressive loss of dopaminergic (DA) neurons. Most PD cases are sporadic; however, rare familial forms have been identified. Autosomal recessive PD (ARPD) results from mutations in Parkin, PINK1, DJ-1, and ATP13A2, while rare, atypical juvenile ARPD result from mutations in FBXO7, DNAJC6, SYNJ1, and PLA2G6. Studying these genes and their function has revealed mitochondrial quality control, protein degradation processes, and oxidative stress responses as common pathways underlying PD pathogenesis...
April 23, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28405187/identification-of-cerebral-metal-ion-imbalance-in-the-brain-of-aging-octodon-degus
#8
Nady Braidy, Anne Poljak, Chris Marjo, Helen Rutlidge, Anne Rich, Bat-Erdene Jugder, Tharusha Jayasena, Nibaldo C Inestrosa, Perminder S Sachdev
The accumulation of redox-active transition metals in the brain and metal dyshomeostasis are thought to be associated with the etiology and pathogenesis of several neurodegenerative diseases, and Alzheimer's disease (AD) in particular. As well, distinct biometal imaging and role of metal uptake transporters are central to understanding AD pathogenesis and aging but remain elusive, due inappropriate detection methods. We therefore hypothesized that Octodon degus develop neuropathological abnormalities in the distribution of redox active biometals, and this effect may be due to alterations in the expression of lysosomal protein, major Fe/Cu transporters, and selected Zn transporters (ZnTs and ZIPs)...
2017: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/28334751/atp13a2-park9-regulates-endo-lysosomal-cargo-sorting-and-proteostasis-through-a-novel-pi-3-5-p2-mediated-scaffolding-function
#9
S Demirsoy, S Martin, S Motamedi, S van Veen, T Holemans, C Van den Haute, A Jordanova, V Baekelandt, P Vangheluwe, P Agostinis
ATP13A2 (also called PARK9), is a transmembrane endo-/lysosomal-associated P5 type transport ATPase. Loss-of-function mutations in ATP13A2 result in the Kufor-Rakeb Syndrome (KRS), a form of autosomal Parkinson's disease (PD). In spite of a growing interest in ATP13A2, very little is known about its physiological role in stressed cells. Recent studies suggest that the N-terminal domain of ATP13A2 may hold key regulatory functions, but their nature remains incompletely understood. To this end, we generated a set of melanoma and neuroblastoma cell lines stably overexpressing wild-type (WT), catalytically inactive (D508N) and N-terminal mutants, or shRNA against ATP13A2...
May 1, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28302480/comprehensive-investigation-of-aberrant-micrornas-expression-in-cells-culture-model-of-mncl2-induced-neurodegenerative-disease
#10
Rong He, Xiaoyun Xie, Linyue Lv, Yongqi Huang, Xianmin Xia, Xiaowu Chen, Lei Zhang
Manganese (Mn) is required in various human physiological processes. Excessive Mn exposure causes manganism, a progressive neurodegenerative disorder similar to idiopathic Parkinson's disease (IPD). However, the detailed mechanism of Mn-induced neurotoxicity is not yet fully understood. MicroRNAs (miRNAs) play important roles in gene expression regulation, and miRNA expression profile provides additional biological and prognostic information of diseases. In our study, RNA sequencing was performed to profile miRNAs in the SH-SY5Y cells following MnCl2 treatment...
April 29, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28137957/loss-of-function-mutations-in-the-atp13a2-park9-gene-cause-complicated-hereditary-spastic-paraplegia-spg78
#11
Alejandro Estrada-Cuzcano, Shaun Martin, Teodora Chamova, Matthis Synofzik, Dagmar Timmann, Tine Holemans, Albena Andreeva, Jennifer Reichbauer, Riet De Rycke, Dae-In Chang, Sarah van Veen, Jean Samuel, Ludger Schöls, Thorsten Pöppel, Danny Mollerup Sørensen, Bob Asselbergh, Christine Klein, Stephan Zuchner, Albena Jordanova, Peter Vangheluwe, Ivailo Tournev, Rebecca Schüle
Hereditary spastic paraplegias are heterogeneous neurodegenerative disorders characterized by progressive spasticity of the lower limbs due to degeneration of the corticospinal motor neurons. In a Bulgarian family with three siblings affected by complicated hereditary spastic paraplegia, we performed whole exome sequencing and homozygosity mapping and identified a homozygous p.Thr512Ile (c.1535C > T) mutation in ATP13A2. Molecular defects in this gene have been causally associated with Kufor-Rakeb syndrome (#606693), an autosomal recessive form of juvenile-onset parkinsonism, and neuronal ceroid lipofuscinosis (#606693), a neurodegenerative disorder characterized by the intracellular accumulation of autofluorescent lipopigments...
February 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28131822/genome-scale-networks-link-neurodegenerative-disease-genes-to-%C3%AE-synuclein-through-specific-molecular-pathways
#12
Vikram Khurana, Jian Peng, Chee Yeun Chung, Pavan K Auluck, Saranna Fanning, Daniel F Tardiff, Theresa Bartels, Martina Koeva, Stephen W Eichhorn, Hadar Benyamini, Yali Lou, Andy Nutter-Upham, Valeriya Baru, Yelena Freyzon, Nurcan Tuncbag, Michael Costanzo, Bryan-Joseph San Luis, David C Schöndorf, M Inmaculada Barrasa, Sepehr Ehsani, Neville Sanjana, Quan Zhong, Thomas Gasser, David P Bartel, Marc Vidal, Michela Deleidi, Charles Boone, Ernest Fraenkel, Bonnie Berger, Susan Lindquist
Numerous genes and molecular pathways are implicated in neurodegenerative proteinopathies, but their inter-relationships are poorly understood. We systematically mapped molecular pathways underlying the toxicity of alpha-synuclein (α-syn), a protein central to Parkinson's disease. Genome-wide screens in yeast identified 332 genes that impact α-syn toxicity. To "humanize" this molecular network, we developed a computational method, TransposeNet. This integrates a Steiner prize-collecting approach with homology assignment through sequence, structure, and interaction topology...
February 22, 2017: Cell Systems
https://www.readbyqxmd.com/read/27997702/impulse-control-disorder-lysosomal-malfunction-and-atp13a2-insufficiency-in-parkinsonism
#13
REVIEW
Jun-Ping Liu, Jianfeng Li, Yanhua Lu, Lihui Wang, Gang Chen
Lysosomal transport of cargos in neurons is essential for neuronal proteostasis, transmission and functional motors and behaviours. Lysosomal malfunction including storage disorders is involved in the pathogenesis of Parkinson's disease (PD). Given the unclear molecular mechanisms of diverse defects in PD phenotypes, especially behavioural deficits, this mini review explores the cellular contexts of PD impulse control disorders and the molecular aspects of lysosomal cross-membrane transports. Focuses are paid to trace metal involvements in α-synuclein assembly in Lewy bodies, the functions and molecular interactions of ATP13A2 as ATPase transporters in lysosomal membranes for cross-membrane trafficking and lysosomal homeostasis, and our current understandings of the neural circuits in ICD...
February 2017: Clinical and Experimental Pharmacology & Physiology
https://www.readbyqxmd.com/read/27881166/using-the-social-amoeba-dictyostelium-to-study-the-functions-of-proteins-linked-to-neuronal-ceroid-lipofuscinosis
#14
REVIEW
Robert J Huber
Neuronal ceroid lipofuscinosis (NCL), also known as Batten disease, is a debilitating neurological disorder that affects both children and adults. Thirteen genetically distinct genes have been identified that when mutated, result in abnormal lysosomal function and an excessive accumulation of ceroid lipofuscin in neurons, as well as other cell types outside of the central nervous system. The NCL family of proteins is comprised of lysosomal enzymes (PPT1/CLN1, TPP1/CLN2, CTSD/CLN10, CTSF/CLN13), proteins that peripherally associate with membranes (DNAJC5/CLN4, KCTD7/CLN14), a soluble lysosomal protein (CLN5), a protein present in the secretory pathway (PGRN/CLN11), and several proteins that display different subcellular localizations (CLN3, CLN6, MFSD8/CLN7, CLN8, ATP13A2/CLN12)...
November 24, 2016: Journal of Biomedical Science
https://www.readbyqxmd.com/read/27798102/additional-rare-variant-analysis-in-parkinson-s-disease-cases-with-and-without-known-pathogenic-mutations-evidence-for-oligogenic-inheritance
#15
Steven J Lubbe, Valentina Escott-Price, J Raphael Gibbs, Mike A Nalls, Jose Bras, T Ryan Price, Aude Nicolas, Iris E Jansen, Kin Y Mok, Alan M Pittman, James E Tomkins, Patrick A Lewis, Alastair J Noyce, Suzanne Lesage, Manu Sharma, Elena R Schiff, Adam P Levine, Alexis Brice, Thomas Gasser, John Hardy, Peter Heutink, Nicholas W Wood, Andrew B Singleton, Nigel M Williams, Huw R Morris
Oligogenic inheritance implies a role for several genetic factors in disease etiology. We studied oligogenic inheritance in Parkinson's (PD) by assessing the potential burden of additional rare variants in established Mendelian genes and/or GBA, in individuals with and without a primary pathogenic genetic cause in two large independent cohorts totaling 7,900 PD cases and 6,166 controls. An excess (≥30%) of cases with a recognised primary genetic cause had ≥1 additional rare variants in Mendelian PD genes, as compared with no known mutation PD cases (17%) and unaffected controls (16%), supporting our hypothesis...
December 15, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/27770614/lysosomal-storage-of-subunit-c-of-mitochondrial-atp-synthase-in-brain-specific-atp13a2-deficient-mice
#16
Shigeto Sato, Masato Koike, Manabu Funayama, Junji Ezaki, Takahiro Fukuda, Takashi Ueno, Yasuo Uchiyama, Nobutaka Hattori
Kufor-Rakeb syndrome (KRS) is an autosomal recessive form of early-onset parkinsonism linked to the PARK9 locus. The causative gene for KRS is Atp13a2, which encodes a lysosomal type 5 P-type ATPase. We recently showed that KRS/PARK9-linked mutations lead to several lysosomal alterations, including reduced proteolytic processing of cathepsin D in vitro. However, it remains unknown how deficiency of Atp13a2 is connected to lysosomal impairments. To address this issue, we analyzed brain tissues of Atp13a2 conditional-knockout mice, which exhibited characteristic features of neuronal ceroid lipofuscinosis, including accumulation of lipofuscin positive for subunit c of mitochondrial ATP synthase, suggesting that a common pathogenic mechanism underlies both neuronal ceroid lipofuscinosis and Parkinson disease...
December 2016: American Journal of Pathology
https://www.readbyqxmd.com/read/27619535/endolysosomal-dysfunction-in-parkinson-s-disease-recent-developments-and-future-challenges
#17
Lauren R Kett, William T Dauer
Increasingly, genetic, cell biological, and in vivo work emphasizes the role of the endolysosomal system dysfunction in Parkinson's disease pathogenesis. Yet many questions remain about the mechanisms by which primary endolysosomal dysfunction causes PD as well as how the endolysosomal system interacts with α-synuclein-mediated neurotoxicity. We recently described a new mouse model of parkinsonism in which loss of the endolysosomal protein Atp13a2 causes behavioral, neuropathological, and biochemical changes similar to those present in human subjects with ATP13A2 mutations...
October 2016: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/27534820/covalent-isg15-conjugation-positively-regulates-the-ubiquitin-e3-ligase-activity-of-parkin
#18
Eunju Im, Lang Yoo, Minju Hyun, Woo Hyun Shin, Kwang Chul Chung
Parkinson's disease (PD) is characterized by selective loss of dopaminergic neurons in the pars compacta of the substantia nigra and accumulation of ubiquitinated proteins in aggregates called Lewy bodies. Several mutated genes have been found in familial PD patients, including SNCA (α-synuclein), PARK2 (parkin), PINK1, PARK7 (DJ-1), LRRK2 and ATP13A2 Many pathogenic mutations of PARK2, which encodes the ubiquitin E3 ligase parkin, result in loss of function, leading to accumulation of parkin substrates and consequently contributing to dopaminergic cell death...
August 2016: Open Biology
https://www.readbyqxmd.com/read/27485256/simple-and-rapid-characterization-of-novel-large-germline-deletions-in-sdhb-sdhc-and-sdhd-related-paraganglioma
#19
A S Hoekstra, B van den Ende, X P Julià, L van Breemen, K Scheurwater, C M Tops, A Malinoc, P Devilee, H P H Neumann, J-P Bayley
Germline mutations in genes encoding subunits of succinate dehydrogenase (SDH) are associated with hereditary paraganglioma and pheochromocytoma. Although most mutations in SDHB, SDHC and SDHD are intraexonic variants, large germline deletions may represent up to 10% of all variants but are rarely characterized at the DNA sequence level. Additional phenotypic effects resulting from deletions that affect neighboring genes are also not understood. We performed multiplex ligation-dependent probe amplification, followed by a simple long-range PCR 'chromosome walking' protocol to characterize breakpoints in 20 SDHx-linked paraganglioma-pheochromocytoma patients...
April 2017: Clinical Genetics
https://www.readbyqxmd.com/read/27399248/high-resolution-arrays-reveal-burden-of-copy-number-variations-on-parkinson-disease-genes-associated-with-increased-disease-risk-in-random-cohorts
#20
Megha N Murthy, Avinash M Veerappa, Keshava B Seshachalam, Nallur B Ramachandra
BACKGROUND: Parkinson disease (PD) is a neurological disease responsible for a considerable rate of mortality and morbidity in the society. Since the symptoms of the disease appear much later than the actual onset of neuron degeneration, a majority of cases remain undiagnosed until the manifestation of the symptoms. OBJECTIVES: In order to investigate the existence of such susceptibility in the population, we analyzed Copy Number Variation (CNV) influences on PD genes in 1715 individuals from 12 different populations...
September 2016: Neurological Research
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