Gene Dosage

Publication Title: 
Journal of Cell Science

Protein with tau-like repeats (PTL-1) is the sole Caenorhabditis elegans homolog of tau and MAP2, which are members of the mammalian family of microtubule-associated proteins (MAPs). In mammalian neurons, tau and MAP2 are segregated, with tau being mainly localised to the axon and MAP2 mainly to the dendrite. In particular, tau plays a crucial role in pathology, as elevated levels lead to the formation of tau aggregates in many neurodegenerative conditions including Alzheimer's disease. We used PTL-1 in C.

Author(s): 
Chew, Yee Lian
Fan, Xiaochen
Gˆtz, J¸rgen
Nicholas, Hannah R.
Publication Title: 
Seminars in Cell & Developmental Biology

The glyoxalase system has been studied since 1913. The biochemical function of this enzymatic system is the metabolism of reactive dicarbonyl metabolites, glyoxal and methylglyoxal, to less reactive products. In the last decade research has shown that methylglyoxal is the precursor of quantitatively important damage to the proteome and genome, forming mainly hydroimidazolone and imidazopurinone adducts in protein and DNA respectively.

Author(s): 
Xue, Mingzhan
Rabbani, Naila
Thornalley, Paul J.
Publication Title: 
Nucleic Acids Research

The rRNA genes in the somatic macronucleus of Tetrahymena thermophila are normally on 21 kb linear palindromic molecules (rDNA). We examined the effect on rRNA gene dosage of transforming T.thermophila macronuclei with plasmid constructs containing a pair of tandemly repeated rDNA replication origin regions unlinked to the rRNA gene. A significant proportion of the plasmid sequences were maintained as high copy circular molecules, eventually consisting solely of tandem arrays of origin regions.

Author(s): 
Pan, W. J.
Blackburn, E. H.
Publication Title: 
Nucleic Acids Research

The rRNA genes in the somatic macronucleus of Tetrahymena thermophila are normally on 21 kb linear palindromic molecules (rDNA). We examined the effect on rRNA gene dosage of transforming T.thermophila macronuclei with plasmid constructs containing a pair of tandemly repeated rDNA replication origin regions unlinked to the rRNA gene. A significant proportion of the plasmid sequences were maintained as high copy circular molecules, eventually consisting solely of tandem arrays of origin regions.

Author(s): 
Pan, W. J.
Blackburn, E. H.
Publication Title: 
Molecular and Cellular Biology

In the ciliated protozoan Tetrahymena thermophila the ribosomal DNA (rDNA) minichromosome replicates partially under cell cycle control and is also subject to a copy number control mechanism. The relationship between rDNA replication and rRNA gene transcription was investigated by the analysis of replication, transcription, and DNA-protein interactions in a mutant rDNA, the rmm3 rDNA.

Author(s): 
Gallagher, R. C.
Blackburn, E. H.
Publication Title: 
Fortschritte Der Neurologie-Psychiatrie

A circumscribed association between copy number variations and the diagnosis of schizophrenia or autism but not bipolar disorder supports the notion of schizophrenia and autism principally representing a disturbed brain development. Data of multiply affected families show certain brain structural (e. g. hippocampal) changes to also be present in their first-grade relatives without leading to psychopathological abnormalities. It thus can be concluded that there exist regional fronto-temporal changes in schizophrenia due to genetically early determined primary vulnerability.

Author(s): 
Falkai, P.
Reich-Erkelenz, D.
Malchow, B.
Schmitt, A.
Majtenyi, K.
Publication Title: 
Pharmacology & Therapeutics

Despite intensive research over many years, the treatment of schizophrenia remains a major health issue. Current and emerging treatments for schizophrenia are based upon the classical dopamine and glutamate hypotheses of disease. Existing first and second generation antipsychotic drugs based upon the dopamine hypothesis are limited by their inability to treat all symptom domains and their undesirable side effect profiles. Third generation drugs based upon the glutamate hypothesis of disease are currently under evaluation but are more likely to be used as add on treatments.

Author(s): 
Winchester, Catherine L.
Pratt, Judith A.
Morris, Brian J.
Publication Title: 
Epigenomics

Imprinted genes and neural stem cells (NSC) play an important role in the developing and mature brain. A central theme of imprinted gene function in NSCs is cell survival and G1 arrest to control cell division, cell-cycle exit, migration and differentiation. Moreover, genomic imprinting can be epigenetically switched off at some genes to ensure stem cell quiescence and differentiation. At the genome scale, imprinted genes are organized in dynamic networks formed by interchromosomal interactions and transcriptional coregulation of imprinted and nonimprinted genes.

Author(s): 
Hoffmann, Anke
Daniel, Guillaume
Schmidt-Edelkraut, Udo
Spengler, Dietmar
Publication Title: 
Molecular Psychiatry

Increased dosage of methyl-CpG-binding protein-2 (MeCP2) results in a dramatic neurodevelopmental phenotype with onset at birth. We generated induced pluripotent stem cells (iPSCs) from patients with the MECP2 duplication syndrome (MECP2dup), carrying different duplication sizes, to study the impact of increased MeCP2 dosage in human neurons. We show that cortical neurons derived from these different MECP2dup iPSC lines have increased synaptogenesis and dendritic complexity.

Author(s): 
Nageshappa, S.
Carromeu, C.
Trujillo, C. A.
Mesci, P.
Espuny-Camacho, I.
Pasciuto, E.
Vanderhaeghen, P.
Verfaillie, C. M.
Raitano, S.
Kumar, A.
Carvalho, C. M. B.
Bagni, C.
Ramocki, M. B.
Araujo, B. H. S.
Torres, L. B.
Lupski, J. R.
Van Esch, H.
Muotri, A. R.
Publication Title: 
Lancet (London, England)

BACKGROUND: The borders of Thailand harbour the world's most multidrug resistant Plasmodium falciparum parasites. In 1984 mefloquine was introduced as treatment for uncomplicated falciparum malaria, but substantial resistance developed within 6 years. A combination of artesunate with mefloquine now cures more than 95% of acute infections. For both treatment regimens, the underlying mechanisms of resistance are not known.

Author(s): 
Price, Ric N.
Uhlemann, Anne-Catrin
Brockman, Alan
McGready, Rose
Ashley, Elizabeth
Phaipun, Lucy
Patel, Rina
Laing, Kenneth
Looareesuwan, Sornchai
White, Nicholas J.
Nosten, François
Krishna, Sanjeev

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