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https://www.readbyqxmd.com/read/27881166/using-the-social-amoeba-dictyostelium-to-study-the-functions-of-proteins-linked-to-neuronal-ceroid-lipofuscinosis
#1
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
#2
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 recognized 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...
October 18, 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
#3
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/27619535/endolysosomal-dysfunction-in-parkinson-s-disease-recent-developments-and-future-challenges
#4
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
#5
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
#6
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/27399248/high-resolution-arrays-reveal-burden-of-copy-number-variations-on-parkinson-disease-genes-associated-with-increased-disease-risk-in-random-cohorts
#7
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
https://www.readbyqxmd.com/read/27331115/data-in-support-of-qpcr-primer-design-and-verification-in-a-pink1-rat-model-of-parkinson-disease
#8
Cynthia A Kelm-Nelson, Sharon A Stevenson, Michelle R Ciucci
Datasets provided in this article represent the Rattus norvegicus primer design and verification used in Pink1 -/- and wildtype Long Evans brain tissue. Accessible tables include relevant information, accession numbers, sequences, temperatures and product length, describing primer design specific to the transcript amplification use. Additionally, results of Sanger sequencing of qPCR reaction products (FASTA aligned sequences) are presented for genes of interest. Results and further interpretation and discussion can be found in the original research article "Atp13a2 expression in the periaqueductal gray is decreased in the Pink1 -/- rat model of Parkinson disease" [1]...
September 2016: Data in Brief
https://www.readbyqxmd.com/read/27294386/genetic-mutation-analysis-of-parkinson-s-disease-patients-using-multigene-next-generation-sequencing-panels
#9
Ana Gorostidi, José Félix Martí-Massó, Alberto Bergareche, Mari Cruz Rodríguez-Oroz, Adolfo López de Munain, Javier Ruiz-Martínez
BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting millions of people. Genome-wide association studies (GWAS) have found >25 genetic risk factors and at least 15 loci directly associated with PD. Recent advances in new next-generation DNA sequencing technologies, such as the semiconductor-based Ion Torrent platform, make multigene sequencing cheaper, faster, and more reliable. OBJECTIVES: Our objective was to test the power of this next-generation sequencing technology to analyze large samples by screening the majority of the most relevant PD-related genes known for single and compound mutations...
October 2016: Molecular Diagnosis & Therapy
https://www.readbyqxmd.com/read/27282395/a-familial-atp13a2-mutation-enhances-alpha-synuclein-aggregation-and-promotes-cell-death
#10
Tomás Lopes da Fonseca, Raquel Pinho, Tiago F Outeiro
Aberrant protein-protein interactions are a common pathological hallmark among neurodegenerative diseases, including Parkinson's disease (PD). Thus far, mutations in more than 20 genes have been associated with PD. These genes encode for proteins involved in distinct intracellular pathways, complicating our understanding of the precise molecular mechanisms underlying the disease. Recent reports suggested that the endolysosomal protein ATP13A2 can determine the fate of alpha-synuclein (α-Syn), although no consensus has yet been reached on the mechanisms underlying this effect...
June 8, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/27278822/the-parkinson-s-disease-associated-genes-atp13a2-and-syt11-regulate-autophagy-via-a-common-pathway
#11
Carla F Bento, Avraham Ashkenazi, Maria Jimenez-Sanchez, David C Rubinsztein
Forms of Parkinson's disease (PD) are associated with lysosomal and autophagic dysfunction. ATP13A2, which is mutated in some types of early-onset Parkinsonism, has been suggested as a regulator of the autophagy-lysosome pathway. However, little is known about the ATP13A2 effectors and how they regulate this pathway. Here we show that ATP13A2 depletion negatively regulates another PD-associated gene (SYT11) at both transcriptional and post-translational levels. Decreased SYT11 transcription is controlled by a mechanism dependent on MYCBP2-induced ubiquitination of TSC2, which leads to mTORC1 activation and decreased TFEB-mediated transcription of SYT11, while increased protein turnover is regulated by SYT11 ubiquitination and degradation...
2016: Nature Communications
https://www.readbyqxmd.com/read/27217339/genetic-and-phenotypic-characterization-of-complex-hereditary-spastic-paraplegia
#12
Eleanna Kara, Arianna Tucci, Claudia Manzoni, David S Lynch, Marilena Elpidorou, Conceicao Bettencourt, Viorica Chelban, Andreea Manole, Sherifa A Hamed, Nourelhoda A Haridy, Monica Federoff, Elisavet Preza, Deborah Hughes, Alan Pittman, Zane Jaunmuktane, Sebastian Brandner, Georgia Xiromerisiou, Sarah Wiethoff, Lucia Schottlaender, Christos Proukakis, Huw Morris, Tom Warner, Kailash P Bhatia, L V Prasad Korlipara, Andrew B Singleton, John Hardy, Nicholas W Wood, Patrick A Lewis, Henry Houlden
The hereditary spastic paraplegias are a heterogeneous group of degenerative disorders that are clinically classified as either pure with predominant lower limb spasticity, or complex where spastic paraplegia is complicated with additional neurological features, and are inherited in autosomal dominant, autosomal recessive or X-linked patterns. Genetic defects have been identified in over 40 different genes, with more than 70 loci in total. Complex recessive spastic paraplegias have in the past been frequently associated with mutations in SPG11 (spatacsin), ZFYVE26/SPG15, SPG7 (paraplegin) and a handful of other rare genes, but many cases remain genetically undefined...
July 2016: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/27165006/clinical-exome-sequencing-for-cerebellar-ataxia-and-spastic-paraplegia-uncovers-novel-gene-disease-associations-and-unanticipated-rare-disorders
#13
Bart P van de Warrenburg, Meyke I Schouten, Susanne T de Bot, Sascha Vermeer, Rowdy Meijer, Maartje Pennings, Christian Gilissen, Michèl Aap Willemsen, Hans Scheffer, Erik-Jan Kamsteeg
Cerebellar ataxia (CA) and hereditary spastic paraplegia (HSP) are two of the most prevalent motor disorders with extensive locus and allelic heterogeneity. We implemented clinical exome sequencing, followed by filtering data for a 'movement disorders' gene panel, as a generic test to increase variant detection in 76 patients with these disorders. Segregation analysis or phenotypic re-evaluation was utilized to substantiate findings. Disease-causing variants were identified in 9 of 28 CA patients, and 8 of 48 HSP patients...
October 2016: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/27073711/protection-against-mitochondrial-and-metal-toxicity-depends-on-functional-lipid-binding-sites-in-atp13a2
#14
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/27057733/atp13a2-expression-in-the-periaqueductal-gray-is-decreased-in-the-pink1-rat-model-of-parkinson-disease
#15
Cynthia A Kelm-Nelson, Sharon A Stevenson, Michelle R Ciucci
Vocal communication deficits are common in Parkinson disease (PD). Widespread alpha-synuclein pathology is a common link between familial and sporadic PD, and recent genetic rat models based on familial genetic links increase the opportunity to explore vocalization deficits and their associated neuropathologies. Specifically, the Pink1 knockout (-/-) rat presents with early, progressive motor deficits, including significant vocal deficits, at 8 months of age. Moreover, this rat model exhibits alpha-synuclein pathology compared to age-matched non-affected wildtype (WT) controls...
May 16, 2016: Neuroscience Letters
https://www.readbyqxmd.com/read/27039055/loss-of-atp13a2-impairs-glycolytic-function-in-kufor-rakeb-syndrome-patient-derived-cell-models
#16
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/27001088/exonic-rearrangements-in-the-known-parkinson-s-disease-causing-genes-are-a-rare-cause-of-the-disease-in-south-african-patients
#17
Celia van der Merwe, Jonathan Carr, Brigitte Glanzmann, Soraya Bardien
Parkinson's disease (PD) is a neurodegenerative movement disorder characterized by the loss of dopaminergic neurons in the substantia nigra of the midbrain. To date, a number of PD-causing genes have been found, including SNCA, LRRK2, VPS35, PARK2, PINK1, DJ-1, ATP13A2, and most recently CHCHD2. Mutations in these genes range from point mutations to larger exonic rearrangements including deletions and duplications. This study aimed to detect possible copy number variation (CNV) in the known PD-causing genes in a cohort of South African patients with PD...
April 21, 2016: Neuroscience Letters
https://www.readbyqxmd.com/read/26993503/%C3%AE-synuclein-in-extracellular-vesicles-functional-implications-and-diagnostic-opportunities
#18
REVIEW
Camilla Lööv, Clemens R Scherzer, Bradley T Hyman, Xandra O Breakefield, Martin Ingelsson
Fibrillar inclusions of intraneuronal α-synuclein can be detected in certain brain areas from patients with Parkinson's disease (PD) and other disorders with Lewy body pathology. These insoluble protein aggregates do not themselves appear to have a prominent neurotoxic effect, whereas various α-synuclein oligomers appear harmful. Although it is incompletely known how the prefibrillar species may be pathogenic, they have been detected both within and on the outside of exosomes and other extracellular vesicles (EVs), suggesting that such structures may mediate toxic α-synuclein propagation between neurons...
April 2016: Cellular and Molecular Neurobiology
https://www.readbyqxmd.com/read/26965689/hereditary-parkinsonism-associated-genetic-variations-in-park9-locus-lead-to-functional-impairment-of-atpase-type-13a2
#19
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/26965686/other-proteins-involved-in-parkinson-s-disease-and-related-disorders
#20
Fernando Cardona, Jordi Pérez-Tur
In order to explain the molecular causes of Parkinson's Disease (PD) it is important to understand the effect that mutations described as causative of the disease have at the functional level. In this special issue, several authors have been reviewing the effects in PD and other parkinsonisms of mutations described in LRRK2, α-synuclein, PINK1-Parkin-DJ-1, UCHL1, ATP13A2, GBA, VPS35, FBOX7 and HTRA2. In this review, we compile the knowledge about other proteins with a more general role in neurodegenerative diseases (MAPT) or for which less data is available due to its recent discovery (EIF4G1, DNAJC13), the lack of structural or functional data (as for PLA2G6 or DNAJC6), or even their doubtful association with the disease (as for GIGYF2, SYNJ1 and SPR)...
March 11, 2016: Current Protein & Peptide Science
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