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https://www.readbyqxmd.com/read/27770614/lysosomal-storage-of-subunit-c-of-mitochondrial-atp-synthase-in-brain-specific-atp13a2-deficient-mice
#1
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...
October 19, 2016: American Journal of Pathology
https://www.readbyqxmd.com/read/27485256/simple-and-rapid-characterization-of-novel-large-germline-deletions-in-sdhb-sdhc-and-sdhd-related-paraganglioma
#2
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...
August 3, 2016: Clinical Genetics
https://www.readbyqxmd.com/read/27073711/protection-against-mitochondrial-and-metal-toxicity-depends-on-functional-lipid-binding-sites-in-atp13a2
#3
Shaun Martin, Sarah van Veen, Tine Holemans, Seyma Demirsoy, Chris van den Haute, Veerle Baekelandt, Patrizia Agostinis, Jan Eggermont, Peter Vangheluwe
The late endo-/lysosomal P-type ATPase ATP13A2 (PARK9) is implicated in Parkinson's disease (PD) and Kufor-Rakeb syndrome, early-onset atypical Parkinsonism. ATP13A2 interacts at the N-terminus with the signaling lipids phosphatidic acid (PA) and phosphatidylinositol (3,5) bisphosphate (PI(3,5)P2), which modulate ATP13A2 activity under cellular stress conditions. Here, we analyzed stable human SHSY5Y cell lines overexpressing wild-type (WT) or ATP13A2 mutants in which three N-terminal lipid binding sites (LBS1-3) were mutated...
2016: Parkinson's Disease
https://www.readbyqxmd.com/read/27039055/loss-of-atp13a2-impairs-glycolytic-function-in-kufor-rakeb-syndrome-patient-derived-cell-models
#4
Jin-Sung Park, Brianada Koentjoro, Ryan L Davis, Carolyn M Sue
BACKGROUND: Kufor-Rakeb syndrome (KRS) is an autosomal recessive, juvenile-onset Parkinson's disease (PD) caused by loss-of-function mutations in ATP13A2 (PARK9). Impaired energy metabolism is considered a pathogenic mechanism in PD and mitochondrial dysfunction resulting from Zn(2+) dyshomeostasis has been found in KRS patient-derived cells. In addition to mitochondrial energy production, glycolysis plays an important role in cellular energy metabolism and glucose hypometabolism has been reported in PD...
June 2016: Parkinsonism & related Disorders
https://www.readbyqxmd.com/read/26965689/hereditary-parkinsonism-associated-genetic-variations-in-park9-locus-lead-to-functional-impairment-of-atpase-type-13a2
#5
Jin-Sung Park, Carolyn M Sue
Kufor-Rakeb syndrome (KRS) is an autosomal recessive form of Parkinson's disease (PD) with juvenile onset of parkinsonism, often accompanied by extra clinical features such as supranuclear gaze palsy, dementia and generalised brain atrophy. Mutations in ATP13A2, associated with the PARK9 locus (chromosome 1p36) have been identified in KRS patients. ATP13A2 encodes a lysosomal P5B-type ATPase which has functional domains similar to other P-type ATPases which mainly transport cations. Consistently, recent studies suggest that human ATP13A2 may preferably regulate Zn2+, while ATP13A2 from other species have different substrate selectivity...
March 11, 2016: Current Protein & Peptide Science
https://www.readbyqxmd.com/read/26885710/manganism-and-parkinson-s-disease-mn-ii-and-zn-ii-interaction-with-a-30-amino-acid-fragment
#6
Maurizio Remelli, Massimiliano Peana, Serenella Medici, Malgorzata Ostrowska, Elzbieta Gumienna-Kontecka, Maria Antonietta Zoroddu
A protected 30-amino acid fragment, Acetyl-SPDEKHELMIQLQKLDYTVGFCGDGANDCG-Amide, Acetyl-Ser-Pro-Asp-Glu-Lys-His-Glu-Leu-Met-Ile-Gln-Leu-Gln-Lys-Leu-Asp-Tyr-Thr-Val-Gly-Phe-Cys-Gly-Asp-Gly-Ala-Asn-Asp-Cys-Gly-Amide, encompassing the sequence from residues 1164 to 1193 in the encoded protein from Parkinson's disease gene Park9 (YPk9), was studied for manganese and zinc binding. Manganese exposure is considered to be an environmental risk factor connected to PD and PD-like syndrome. Research into the genetic and environmental risk factors involved in disease susceptibility has recently uncovered a link existing between Park9 and manganese...
March 28, 2016: Dalton Transactions: An International Journal of Inorganic Chemistry
https://www.readbyqxmd.com/read/26848562/atp13a2-deficiency-aggravates-astrocyte-mediated-neuroinflammation-via-nlrp3-inflammasome-activation
#7
Chen Qiao, Nuo Yin, Huan-Yu Gu, Jia-Lei Zhu, Jian-Hua Ding, Ming Lu, Gang Hu
AIM: Atp13a2 (Park9) gene encodes a transmembrane lysosomal P5-type ATPase (ATP13A2), and its missense or truncation mutations leads to lysosomal dysfunction and consequently results in neuronal death in the pathogenesis of Parkinson's disease (PD). Nevertheless, the roles of ATP13A2 in the biological features of astrocytes, especially in the regulation of PD-related neuroinflammation, have not been investigated. METHODS: We cultured primary neurons and astrocytes from mouse midbrain to investigate the mechanisms for astrocyte ATP13A2-regulated lysosomal function and neuroinflammation following 1-methyl-4-phenylpyridinium (MPP(+) ) treatment...
June 2016: CNS Neuroscience & Therapeutics
https://www.readbyqxmd.com/read/26245297/status-of-the-parkinson-s-disease-gene-family-expression-in-non-small-cell-lung-cancer
#8
Quan Xing Liu, Hong Zheng, Xu Feng Deng, Dong Zhou, Ji Gang Dai
BACKGROUND: The purpose of this study is to detect the Parkinson's disease gene family mRNA relative expression in the non-small-cell lung cancer (NSCLC) tumor tissue and analyze the association between tumor characteristics and the Parkinson's disease gene family. METHODS: Tumor tissue and tumor-adjacent tissue of 114 NSCLC patients were collected and SYBR quantitative analysis was used to detect the relative expression level of nine Parkinson's disease gene mRNAs...
2015: World Journal of Surgical Oncology
https://www.readbyqxmd.com/read/26023759/a-current-review-for-biological-monitoring-of-manganese-with-exposure-susceptibility-and-response-biomarkers
#9
REVIEW
Gyuri Kim, Ho-Sun Lee, Joon Seok Bang, Boram Kim, Dahae Ko, Mihi Yang
People can be easily exposed to manganese (Mn), the twelfth most abundant element, through various exposure routes. However, overexposure to Mn causes manganism, a motor syndrome similar to Parkinson disease, via interference of the several neurotransmitter systems, particularly the dopaminergic system in areas. At cellular levels, Mn preferentially accumulates in mitochondria and increases the generation of reactive oxygen species, which changes expression and activity of manganoproteins. Many studies have provided invaluable insights into the causes, effects, and mechanisms of the Mn-induced neurotoxicity...
2015: Journal of Environmental Science and Health. Part C, Environmental Carcinogenesis & Ecotoxicology Reviews
https://www.readbyqxmd.com/read/25912790/the-parkinson-associated-human-p5b-atpase-atp13a2-protects-against-the-iron-induced-cytotoxicity
#10
Débora E Rinaldi, Gerardo R Corradi, Lucía Martínez Cuesta, Hugo P Adamo, Felicitas de Tezanos Pinto
P-type ion pumps are membrane transporters that have been classified into five subfamilies termed P1-P5. The ion transported by the P5-ATPases is not known. Five genes named ATP13A1-ATP13A5 that belong to the P5-ATPase group are present in humans. Loss-of-function mutations in the ATP13A2 gene (PARK9, OMIM 610513) underlay a form of Parkinson's disease (PD) known as the Kufor-Rakeb syndrome (KRS), which belongs to the group of syndromes of neurodegeneration with brain iron accumulation (NBIA). Here we report that the cytotoxicity induced by iron exposure was two-fold reduced in CHO cells stably expressing the ATP13A2 recombinant protein (ATP13A2)...
August 2015: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/25548536/atp13a2-park9-deficiency-neither-cause-lysosomal-impairment-nor-alter-%C3%AE-synuclein-metabolism-in-sh-sy5y-cells
#11
Eun-Jin Bae, Cheolsoon Lee, He-Jin Lee, Seokjoong Kim, Seung-Jae Lee
Parkinson's disease is a multifactorial disorder with several genes linked to the familial types of the disease. ATP13A2 is one of those genes and encode for a transmembrane protein localized in lysosomes and late endosomes. Previous studies suggested the roles of this protein in lysosomal functions and cellular ion homeostasis. Here, we set out to investigate the role of ATP13A2 in lysosomal function and in metabolism of α-synuclein, another PD-linked protein whose accumulation is implicated in the pathogenesis...
December 2014: Experimental Neurobiology
https://www.readbyqxmd.com/read/25461191/%C3%AE-synuclein-induced-dopaminergic-neurodegeneration-in-a-rat-model-of-parkinson-s-disease-occurs-independent-of-atp13a2-park9
#12
Guillaume Daniel, Alessandra Musso, Elpida Tsika, Aris Fiser, Liliane Glauser, Olga Pletnikova, Bernard L Schneider, Darren J Moore
Mutations in the ATP13A2 (PARK9) gene cause early-onset, autosomal recessive Parkinson's disease (PD) and Kufor-Rakeb syndrome. ATP13A2 mRNA is spliced into three distinct isoforms encoding a P5-type ATPase involved in regulating heavy metal transport across vesicular membranes. Here, we demonstrate that three ATP13A2 mRNA isoforms are expressed in the normal human brain and are modestly increased in the cingulate cortex of PD cases. ATP13A2 can mediate protection toward a number of stressors in mammalian cells and can protect against α-synuclein-induced toxicity in cellular and invertebrate models of PD...
January 2015: Neurobiology of Disease
https://www.readbyqxmd.com/read/25392495/atp13a2-park9-regulates-secretion-of-exosomes-and-%C3%AE-synuclein
#13
Taiji Tsunemi, Kana Hamada, Dimitri Krainc
Kufor-Rakeb syndrome (KRS) is caused by loss-of-function mutations in ATP13A2 (PARK9) and characterized by juvenile-onset parkinsonism, pyramidal signs, and cognitive decline. Previous studies suggested that PARK9 deficiency causes lysosomal dysfunction and α-synuclein (α-syn) accumulation, whereas PARK9 overexpression suppresses toxicity of α-syn. However, the precise mechanism of PARK9 effect on lysosomes and α-syn has been unknown. Here, we found that overexpressed PARK9 localized to multivesicular bodies (MVBs) in the human H4 cell line...
November 12, 2014: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/25374329/analysis-of-thr12met-and-ala1144thr-mutations-of-the-atp13a2-gene-in-parkinson-s-disease-patients-in-xinjiang-uygur-and-han-ethnic-groups
#14
Guihua Li, Zhenzhong Zhang, Huan Xia, Xinling Yang
BACKGROUND: It has been reported that the ATP13A2 gene is one of the most susceptible pathogenic genes of Parkinson's disease (PD). PARK9 mutations are found in early-onset PD and familial PD patients. Uygur and Han PD patients in the Xinjiang area were recruited as research subjects to study the differences in the Thr12Met and Ala1144Thr loci mutations of the ATP13A2 gene in these PD populations. This study explored the mutations at the Thr12Met and Ala1144Thr gene loci of the ATP13A2 gene in Parkinson's disease patients in the Uygur and Han populations in the Xinjiang province...
2014: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/25197640/mutations-in-the-atp13a2-gene-and-parkinsonism-a-preliminary-review
#15
REVIEW
Xinglong Yang, Yanming Xu
Parkinson's disease (PD) is a major neurodegenerative disorder for which the etiology and pathogenesis remain as elusive as for Alzheimer's disease. PD appears to be caused by genetic and environmental factors, and pedigree and cohort studies have identified numerous susceptibility genes and loci related to PD. Autosomal recessive mutations in the genes Parkin, Pink1, DJ-1, ATP13A2, PLA2G6, and FBXO7 have been linked to PD susceptibility. Such mutations in ATP13A2, also named PARK9, were first identified in 2006 in a Chilean family and are associated with a juvenile-onset, levodopa-responsive type of Parkinsonism called Kufor-Rakeb syndrome (KRS)...
2014: BioMed Research International
https://www.readbyqxmd.com/read/24790577/interaction-of-cu-ii-and-ni-ii-with-ypk9-protein-fragment-via-nmr-studies
#16
Massimiliano Francesco Peana, Serenella Medici, Alessia Ledda, Valeria Marina Nurchi, Maria Antonietta Zoroddu
P₁D₂E₃K₄H₅E₆L₇ (PK9-H), a fragment of Ypk9, the yeast homologue of the human Park9 protein, was studied for its coordination abilities towards Ni(II) and Cu(II) ions through mono- and bi-dimensional NMR techniques. Both proteins are involved in the transportation of metal ions, including manganese and nickel, from the cytosol to the lysosomal lumen. Ypk9 showed manganese detoxification role, preventing a Mn-induced Parkinsonism (PD) besides mutations in Park9, linked to a juvenile form of the disease...
2014: TheScientificWorldJournal
https://www.readbyqxmd.com/read/24742361/orchestrated-increase-of-dopamine-and-park-mrnas-but-not-mir-133b-in-dopamine-neurons-in-parkinson-s-disease
#17
COMPARATIVE STUDY
Falk Schlaudraff, Jan Gründemann, Michael Fauler, Elena Dragicevic, John Hardy, Birgit Liss
Progressive loss of substantia nigra dopamine neurons (SN DA) is a hallmark of aging and of Parkinson's disease (PD). Mutations in PARK genes cause familial PD forms. Increased expression of alpha-synuclein (PARK4) is a disease-triggering event in familial PD and also observed in SN DA neurons in sporadic PD but related transcriptional changes are unknown. With optimized single-cell quantitative real-time polymerase chain reaction analysis, we compared messenger RNA and microRNA levels in SN DA neurons from sporadic PD patients and controls...
October 2014: Neurobiology of Aging
https://www.readbyqxmd.com/read/24729340/low-prevalence-of-most-frequent-pathogenic-variants-of-six-park-genes-in-sporadic-parkinson-s-disease
#18
Silvia García, Luz Berenice López-Hernández, Juan Antonio Suarez-Cuenca, Marlene Solano-Rojas, Martha P Gallegos-Arreola, Olga Gama-Moreno, Paulina Valdez-Anguiano, Patricia Canto, Luis Dávila-Maldonado, Carlos F Cuevas-García, Ramón Mauricio Coral-Vázquez
Genetic variants that confer susceptibility to Parkinson's disease (PD) show unbalanced distribution among different populations; genetic predisposition to either familial or sporadic forms of PD in Mexican-mestizo population has not been comprehensively studied. The aim of the present study was to analyze genetic variants in six PARK genes in PD patients. In total 381 individuals (173 patients, 208 controls) were genotyped for p.Gly2019Ser and p.Gly2385Arg variants of LRRK2. The p.Gly2019Ser variant was present in two patients and one healthy control; the p...
2014: Folia Neuropathologica
https://www.readbyqxmd.com/read/24603074/parkinson-s-disease-linked-human-park9-atp13a2-maintains-zinc-homeostasis-and-promotes-%C3%AE-synuclein-externalization-via-exosomes
#19
Stephanie M Y Kong, Brian K K Chan, Jin-Sung Park, Kathryn J Hill, Jade B Aitken, Louise Cottle, Hovik Farghaian, Adam R Cole, Peter A Lay, Carolyn M Sue, Antony A Cooper
α-Synuclein plays a central causative role in Parkinson's disease (PD). Increased expression of the P-type ATPase ion pump PARK9/ATP13A2 suppresses α-Synuclein toxicity in primary neurons. Our data indicate that ATP13A2 encodes a zinc pump; neurospheres from a compound heterozygous ATP13A2(-/-) patient and ATP13A2 knockdown cells are sensitive to zinc, whereas ATP13A2 over-expression in primary neurons confers zinc resistance. Reduced ATP13A2 expression significantly decreased vesicular zinc levels, indicating ATP13A2 facilitates transport of zinc into membrane-bound compartments or vesicles...
June 1, 2014: Human Molecular Genetics
https://www.readbyqxmd.com/read/24399444/parkinson-s-disease-associated-human-atp13a2-park9-deficiency-causes-zinc-dyshomeostasis-and-mitochondrial-dysfunction
#20
Jin-Sung Park, Brianada Koentjoro, David Veivers, Alan Mackay-Sim, Carolyn M Sue
Human ATP13A2 (PARK9), a lysosomal type 5 P-type ATPase, has been associated with autosomal recessive early-onset Parkinson's disease (PD). ATP13A2 encodes a protein that is highly expressed in neurons and is predicted to function as a cation pump, although the substrate specificity remains unclear. Accumulation of zinc and mitochondrial dysfunction are established aetiological factors that contribute to PD; however, their underlying molecular mechanisms are largely unknown. Using patient-derived human olfactory neurosphere cultures, which harbour loss-of-function mutations in both alleles of ATP13A2, we identified a low intracellular free zinc ion concentration ([Zn(2+)]i), altered expression of zinc transporters and impaired sequestration of Zn(2+) into autophagy-lysosomal pathway-associated vesicles, indicating that zinc dyshomeostasis occurs in the setting of ATP13A2 deficiency...
June 1, 2014: Human Molecular Genetics
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