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Young Joon Kwon, Marni J Falk, Michael J Bennett
CLN3 disease (Spielmeyer-Vogt-Sjogren-Batten disease, previously known as classic juvenile neuronal ceroid lipofuscinosis, NCL) is a pediatric-onset progressive neurodegenerative disease characterized by progressive vision loss, seizures, loss of cognitive and motor function, and early death. While no precise biochemical mechanism or therapies are known, the pathogenesis of CLN3 disease involves intracellular calcium accumulation that may trigger apoptosis. Our prior work in in vitro cell models of CLN3 deficiency suggested that FDA-approved calcium channel antagonists may have therapeutic value...
October 20, 2016: Journal of Inherited Metabolic Disease
Delphine Albrecht, Johanna Ceschin, Jim Dompierre, Florian Gueniot, Benoît Pinson, Bertrand Daignan-Fornier
Identifying synthetic lethal interactions has emerged as a promising new therapeutic approach aimed at targeting cancer cells directly. Here, we used the yeast Saccharomyces cerevisiae as a simple eukaryotic model to screen for mutations resulting in a synthetic lethality with 5-Amino-4-Imidazole CarboxAmide Ribonucleoside (AICAR) treatment. Indeed, AICAR has been reported to inhibit the proliferation of multiple cancer cell lines. Here, we found that loss of several histone-modifying enzymes, including Bre1 (histone H2B ubiquitination) and Set1 (histone H3 lysine 4 methylation), greatly enhanced AICAR inhibition on growth via combined-effects of both the drug and the mutations on G1 cyclins...
October 5, 2016: Genetics
Robert J Huber, Michael A Myre, Susan L Cotman
Neuronal ceroid lipofuscinosis (NCL), also known as Batten disease, refers to a group of severe neurodegenerative disorders that primarily affect children. The most common subtype of the disease is caused by loss-of-function mutations in CLN3, which is conserved across model species from yeast to human. The precise function of the CLN3 protein is not known, which has made targeted therapy development challenging. In the social amoeba Dictyostelium discoideum, loss of Cln3 causes aberrant mid-to-late stage multicellular development...
September 26, 2016: Cell Adhesion & Migration
E P Nuzhnyi, A F Yakimovsky, A A Timofeeva, T S Usenko, M A Nikolaev, A K Emel'yanov, V I Amosov, E V Bubnova, A M Bukina, E Yu Zakharova, S N Pchelina
Mutations in the GBA and SMPD1 genes, which lead to the development of lysosomal storage diseases, are high risk factors for Parkinson's disease and dementia with Lewy bodies. We screened the mutations in the GALC and CLN3 genes in patients with Parkinson's disease and control subjects. A heterozygous CLN3 mutation (del 1.02 kb) carrier with clinical features of the unusual extrapyramidal syndrome was identified. A role of CLN3 mutations in the development of neurodegenerative disorders is discussed.
2016: Zhurnal Nevrologii i Psikhiatrii Imeni S.S. Korsakova
Megan E Bosch, Amy Aldrich, Rachel Fallet, Jessica Odvody, Maria Burkovetskaya, Kaitlyn Schuberth, Julie A Fitzgerald, Kevin D Foust, Tammy Kielian
UNLABELLED: Juvenile neuronal ceroid lipofuscinosis (JNCL) is a fatal lysosomal storage disease caused by autosomal-recessive mutations in CLN3 for which no treatment exists. Symptoms appear between 5 and 10 years of age, beginning with blindness and seizures, followed by progressive cognitive and motor decline and premature death (late teens to 20s). We explored a gene delivery approach for JNCL by generating two self-complementary adeno-associated virus 9 (scAAV9) constructs to address CLN3 dosage effects using the methyl-CpG-binding protein 2 (MeCP2) and β-actin promoters to drive low versus high transgene expression, respectively...
September 14, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Hong-Yeoul Ryu, Nicole R Wilson, Sameet Mehta, Soo Seok Hwang, Mark Hochstrasser
Post-translational protein modification by the small ubiquitin-related modifier (SUMO) regulates numerous cellular pathways, including transcription, cell division, and genome maintenance. The SUMO protease Ulp2 modulates many of these SUMO-dependent processes in budding yeast. From whole-genome RNA sequencing (RNA-seq), we unexpectedly discovered that cells lacking Ulp2 display a twofold increase in transcript levels across two particular chromosomes: chromosome I (ChrI) and ChrXII. This is due to the two chromosomes being present at twice their normal copy number...
August 15, 2016: Genes & Development
David E Sleat, Erika Gedvilaite, Yeting Zhang, Peter Lobel, Jinchuan Xing
The neuronal ceroid lipofuscinoses (NCLs) are a group of fatal, mostly recessive neurodegenerative lysosomal storage diseases. While clinically similar, they are genetically distinct and result from mutations in at least twelve different genes. Estimates of NCL incidence range from 0.6 to 14 per 100,000 live births but vary widely between populations and are influenced by whether patients are classified based upon clinical or genetic criteria. We investigated mutations in twelve NCL genes in ~61,000 individuals represented in the Exome Aggregation Consortium (ExAC) whole exome sequencing database...
November 30, 2016: Gene
Helena M Minye, Anna-Liisa Fabritius, Jouni Vesa, Leena Peltonen
The article contains raw and analyzed data related to the research article "Neuronal ceroid lipofuscinosis genes, CLN2, CLN3, CLN5 are spatially and temporally co-expressed in a developing mouse brain" (Fabritius et al., 2014) [1]. The processed data gives an understanding of the development of the cell types that are mostly affected by defective function of CLN proteins, timing of expression of CLN1, CLN2, CLN3 and CLN5 genes in a murine model. The data shows relationship between the expression pattern of these genes during neural development...
September 2016: Data in Brief
Erika F Augustine, Jonathan W Mink
Abstract Juvenile Neuronal Ceroid Lipofuscinosis is a lysosomal storage disease characterized pathologically by intracellular accumulation of autofluorescent storage material and neurodegeneration. Caused by mutations in the CLN3 gene on chromosome 16p12, the precise functions of the encoded protein remain unclear. Yet, recent preclinical discovery has established new therapeutic targets in development, including immunosuppressants, anti-inflammatories, and gene replacement therapies. Development of robust clinical trial endpoints appropriate for this poly-symptomatic disease, clinical trial design optimized for small samples, and adequate and efficient participant recruitment are challenges that lay ahead...
June 2016: Pediatric Endocrinology Reviews: PER
Markus N Preising, Michaela Abura, Melanie Jäger, Klaus-Heiko Wassill, Birgit Lorenz
PURPOSE: CLN3 is a rare lysosomal storage disorder. The majority of the patients suffer from neurological degeneration in the first decade of life leading to death in the second or third decade. One of the first symptoms is a rapid visual decline from retinal degeneration. The aim of this study was to correlate the retinal changes in CLN3 as seen with spectral domain optical coherence tomography (SD-OCT) with functional data in patients in the first years after the subjective onset of ocular symptoms...
August 2, 2016: Ophthalmic Genetics
Sandra Oetjen, Dietmar Kuhl, Guido Hermey
Juvenile Neuronal Ceroid Lipofuscinosis (JNCL), the most common neurodegenerative disease affecting children, is caused by mutations of the CLN3 gene encoding CLN3, a transmembrane protein with so far undefined function. The embryonic expression of the gene has not been studied in detail before. Moreover, the protein CLN3 was mostly localized on the subcellular level to lysosomes but the exclusiveness is still under debate. Here, we analyze the expression pattern of murine CLN3 at different developmental stages by in situ hybridizations...
July 25, 2016: Journal of Neurochemistry
Luke Aaron Wiley, Erin Burnight, Arlene V Drack, Bailey B Banach, Dalyz Ochoa, Cathryn M Cranston, Robert A Madumba, Jade S East, Robert F Mullins, Edwin Stone, Budd A Tucker
Juvenile neuronal ceroid lipofuscinosis (JNCL) is a childhood neurodegenerative disease with early-onset, severe central vision loss. Affected children develop seizures and central nervous system degeneration accompanied by severe motor and cognitive deficits. There is no cure for JNCL and patients usually die during the second or third decade of life. In this study, independent lines of induced pluripotent stem cells (iPSCs) were generated from two patients with molecularly confirmed mutations in CLN3, the gene mutated in JNCL...
July 11, 2016: Human Gene Therapy
Kim Wager, Anselm A Zdebik, Sonia Fu, Jonathan D Cooper, Robert J Harvey, Claire Russell
The neuronal ceroid lipofuscinoses are a group of lysosomal storage disorders that comprise the most common, genetically heterogeneous, fatal neurodegenerative disorders of children. They are characterised by childhood onset, visual failure, epileptic seizures, psychomotor retardation and dementia. CLN3 disease, also known as Batten disease, is caused by autosomal recessive mutations in the CLN3 gene, 80-85% of which are a ~1 kb deletion. Currently no treatments exist, and after much suffering, the disease inevitably results in premature death...
2016: PloS One
Ewa Pronicka, Dorota Piekutowska-Abramczuk, Elżbieta Ciara, Joanna Trubicka, Dariusz Rokicki, Agnieszka Karkucińska-Więckowska, Magdalena Pajdowska, Elżbieta Jurkiewicz, Paulina Halat, Joanna Kosińska, Agnieszka Pollak, Małgorzata Rydzanicz, Piotr Stawinski, Maciej Pronicki, Małgorzata Krajewska-Walasek, Rafał Płoski
BACKGROUND: Whole-exome sequencing (WES) has led to an exponential increase in identification of causative variants in mitochondrial disorders (MD). METHODS: We performed WES in 113 MD suspected patients from Polish paediatric reference centre, in whom routine testing failed to identify a molecular defect. WES was performed using TruSeqExome enrichment, followed by variant prioritization, validation by Sanger sequencing, and segregation with the disease phenotype in the family...
2016: Journal of Translational Medicine
Gewalin Aungaroon, Barbara Hallinan, Puneet Jain, Paul S Horn, Christine Spaeth, Ravindra Arya
BACKGROUND: Neuronal ceroid lipofuscinoses (NCL) are heterogeneous neurodegenerative disorders. A better understanding of genotype-phenotype-histology correlation is expected to improve patient care and enhance understanding for phenotypic variability. This meta-analysis studies the correlation of NCL genotypes with clinical phenotypes, ages of onset, and pathologic findings. METHODS: A structured MEDLINE search was performed using search strings incorporating relevant Medical Subject Headings (MeSH) terms...
July 2016: Pediatric Neurology
Mayu Oomuro, Taku Kato, Yan Zhou, Daisuke Watanabe, Yasuo Motoyama, Hiromi Yamagishi, Takeshi Akao, Masayuki Aizawa
One of the key processes in making beer is fermentation. In the fermentation process, brewer's yeast plays an essential role in both the production of ethanol and the flavor profile of beer. Therefore, the mechanism of ethanol fermentation by of brewer's yeast is attracting much attention. The high ethanol productivity of sake yeast has provided a good basis from which to investigate the factors that regulate the fermentation rates of brewer's yeast. Recent studies found that the elevated fermentation rate of sake Saccharomyces cerevisiae species is closely related to a defective transition from vegetative growth to the quiescent (G0) state...
May 19, 2016: Journal of Bioscience and Bioengineering
M S Breen, A Uhlmann, C M Nday, S J Glatt, M Mitt, A Metsalpu, D J Stein, N Illing
The clinical presentation, course and treatment of methamphetamine (METH)-associated psychosis (MAP) are similar to that observed in schizophrenia (SCZ) and subsequently MAP has been hypothesized as a pharmacological and environmental model of SCZ. However, several challenges currently exist in diagnosing MAP accurately at the molecular and neurocognitive level before the MAP model can contribute to the discovery of SCZ biomarkers. We directly assessed subcortical brain structural volumes and clinical parameters of MAP within the framework of an integrative genome-wide RNA-Seq blood transcriptome analysis of subjects diagnosed with MAP (N=10), METH dependency without psychosis (MA; N=10) and healthy controls (N=10)...
2016: Translational Psychiatry
André Lacour, David Ellinghaus, Stefan Schreiber, Andre Franke, Tim Becker
MOTIVATION: The functional mechanisms underlying disease association remain unknown for Genome-wide Association Studies (GWAS) susceptibility variants located outside coding regions. Synthesis of effects from multiple surrounding functional variants has been suggested as an explanation of hard-to-interpret findings. We define filter criteria based on linkage disequilibrium measures and allele frequencies which reflect expected properties of synthesizing variant sets. For eligible candidate sets, we search for haplotype markers that are highly correlated with associated variants...
July 15, 2016: Bioinformatics
Samantha L Hersrud, Attila D Kovács, David A Pearce
Mutations of the CLN3 gene lead to juvenile neuronal ceroid lipofuscinosis (JNCL), an autosomal recessive lysosomal storage disorder that causes progressive neurodegeneration in children and adolescents. There is evidence of immune system involvement in pathology that has been only minimally investigated. We characterized bone marrow stem cell-derived antigen presenting cells (APCs), peritoneal macrophages, and leukocytes from spleen and blood, harvested from the Cln3(-/-) mouse model of JNCL. We detected dramatically elevated CD11c surface levels and increased total CD11c protein in Cln3(-/-) cell samples compared to wild type...
July 2016: Biochimica et Biophysica Acta
Pasquale Palumbo, Marco Vanoni, Valerio Cusimano, Stefano Busti, Francesca Marano, Costanzo Manes, Lilia Alberghina
In budding yeast, overcoming of a critical size to enter S phase and the mitosis/mating switch--two central cell fate events--take place in the G1 phase of the cell cycle. Here we present a mathematical model of the basic molecular mechanism controlling the G1/S transition, whose major regulatory feature is multisite phosphorylation of nuclear Whi5. Cln3-Cdk1, whose nuclear amount is proportional to cell size, and then Cln1,2-Cdk1, randomly phosphorylate both decoy and functional Whi5 sites. Full phosphorylation of functional sites releases Whi5 inhibitory activity, activating G1/S transcription...
2016: Nature Communications
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