Biomedical subjects

Boris Rogelj

Publications and source records attributed to Boris Rogelj.

8 recordsLinked to original sources

PubMed2006

The X11/Mint family of adaptor proteins.

The X11 protein family are multidomain proteins composed of a conserved PTB domain and two C-terminal PDZ domains. They are involved in formation of multiprotein complexes and two of the family members, X11alpha and X11beta, are expressed primarily in neurones. Not much is known about the principal function of X11s, but through interactions with other neuronal proteins, they are believed to be involved in regulating neuronal signaling, trafficking and plasticity. Furthermore, they have been shown to modulate processing of APP and accumulation of Abeta, making them potential therapeutic targets for Alzheimer's disease. This article reviews the known interactions of the different X11s and their involvement in Alzheimer's disease.

Adaptor Proteins, Signal Transducing↗

PubMed2006

The X11 proteins, Abeta production and Alzheimer's disease.

Cerebral deposition of amyloid-beta peptide (Abeta) within neuritic plaques is a hallmark pathology of Alzheimer's disease. It is now generally believed that the development of this pathology is central to the pathogenesis of Alzheimer's disease. As such, inhibiting Abeta deposition or removing Abeta deposits once they are formed represent therapeutic targets for Alzheimer's disease. Abeta is derived from a precursor, the amyloid precursor protein (APP), and APP binds to the X11 family of adaptor proteins. Studies from several laboratories have now shown that X11alpha and X11beta (the two neuronal X11s) inhibit APP processing and Abeta production. Exactly how this is achieved is not yet known but recent studies in which other X11 binding partners have been identified are beginning to reveal potential mechanisms.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Brain-specific small nucleolar RNAs.

Small nucleolar RNAs (snoRNAs) are a group of noncoding RNAs that function mainly as guides for modification of ribosomal RNAs (rRNAs) and small nuclear RNAs (snRNAs). A subgroup of snoRNAs was found to be predominantly expressed in the brain; and interestingly, these brain-specific snoRNAs (b-snoRNAs) appear not to be involved in modification of rRNAs and snRNAs, raising the question of what their function and targets might be. Expression studies of b-snoRNAs in mice have shown potential involvement of two b-snoRNAs, MBII-48 and MBII-52, in learning and memory. HBII-52, the human homolog of MBII-52, appears to be involved with regulation of 5-HT(2C) receptor subunit mRNA. Furthermore, several reports link the disruption of expression of a specific b-snoRNA, HBII-85, with a neurobehavioral disorder, Prader-Willi syndrome. This paper reviews the current knowledge of the properties, expression, and functions of b-snoRNAs.

Animals↗

PubMed2006

Heterogeneity in the cysteine protease inhibitor clitocypin gene family.

Clitocypin from the basidiomycete Clitocybe nebularis is the first fungal protein cysteine protease inhibitor to be characterised in detail, yet no information on its molecular genetics is available. Owing to its unique characteristics, it was assigned as the only member of a new family of cysteine protease inhibitors in the MEROPS inhibitor classification. Here we describe the full-length sequence of the clitocypin gene. A BLAST search confirmed its lack of significant sequence similarity to any other gene. The gene is composed of four exons and three short introns and belongs to a small family of closely related genes with more than 90% identity. Sequence variability is evenly distributed in introns and exons and deduced amino acid substitutions are distributed throughout the protein sequence. Basidiocarps collected at two distant locations were examined and the level of heterogeneity found in one basidiocarp is similar to that between the two. Sequencing of the ribosomal DNA spacers from the two basidiocarps confirmed that the heterogeneity observed in the clitocypin gene is not due to evolutionary divergence of the two specimens caused by geographic separation. Clitocypin is expressed in different parts of the basidiocarp and in cultured mycelia in a manner suggesting regulation by developmental and/or environmental factors.

Amino Acid Sequence↗

PubMed2004

The neuronal adaptor protein X11beta reduces amyloid beta-protein levels and amyloid plaque formation in the brains of transgenic mice.

Accumulation of cerebral amyloid beta-protein (Abeta) is believed to be part of the pathogenic process in Alzheimer's disease. Abeta is derived by proteolytic cleavage from a precursor protein, the amyloid precursor protein (APP). APP is a type-1 membrane-spanning protein, and its carboxyl-terminal intracellular domain binds to X11beta, a neuronal adaptor protein. X11beta has been shown to inhibit the production of Abeta in transfected non-neuronal cells in culture. However, whether this is also the case in vivo in the brain and whether X11beta can also inhibit the deposition of Abeta as amyloid plaques is not known. Here we show that transgenic overexpression of X11beta in neurons leads to a decrease in cerebral Abeta levels in transgenic APPswe Tg2576 mice that are a model of the amyloid pathology of Alzheimer's disease. Moreover, overexpression of X11beta retards amyloid plaque formation in these APPswe mice. Our findings suggest that modulation of X11beta function may represent a novel therapeutic approach for preventing the amyloid pathology of Alzheimer's disease.

Alzheimer Disease↗

PubMed2004

Expression and function of brain specific small RNAs.

Small non-messenger RNAs (snmRNAs) are a heterogeneous group of non-coding RNAs with a variety of regulatory functions including regulation of protein expression and guidance in RNA modifications. They are actively being investigated in Archaebacteria, yeast, invertebrates and mammals. Brain-specific snmRNAs have been identified in mammals and they seem to contribute to neuronal differentiation during development and to brain functions subserving learning and memory. Here we review the current knowledge of the properties, expression and functions of three groups of brain-specific snmRNAs: small nucleolar RNAs, BC1/BC200 RNAs and microRNAs.

Animals↗

PubMed2003

Expression of sea anemone equistatin in potato. Effects of plant proteases on heterologous protein production.

Plants are increasingly used as production platforms of various heterologous proteins, but rapid protein turnover can seriously limit the steady-state expression level. Little is known about specific plant proteases involved in this process. In an attempt to obtain potato (Solanum tuberosum cv Desirée) plants resistant to Colorado potato beetle (Leptinotarsa decemlineata Say) larvae, the protease inhibitor equistatin was expressed under the control of strong, light-inducible and constitutive promoters and was targeted to the secretory pathway with and without endoplasmic reticulum retention signal. All constructs yielded similar stepwise protein degradation patterns, which considerably reduced the amount of active inhibitor in planta and resulted in insufficient levels for resistance against Colorado potato beetle larvae. Affinity purification of the degradation products and N-terminal sequencing allowed the identification of the amino acid P(1)-positions (asparagine [Asn]-13, lysine-56, Asn-82, and arginine-151) that were cleaved in planta. The proteases involved in the equistatin degradation were characterized with synthetic substrates and inhibitors. Kininogen domain 3 completely inhibited equistatin degradation in vitro. The results indicate that arginine/lysine-specific and legumain-type Asn-specific cysteine proteases seriously impede the functional accumulation of recombinant equistatin in planta. General strategies to improve the resistance to proteases of heterologous proteins in plants are proposed.

Amino Acid Sequence↗

PubMed2003

Contextual fear conditioning regulates the expression of brain-specific small nucleolar RNAs in hippocampus.

Some small nucleolar RNAs (snoRNAs) are exclusively expressed in the brain but they have no known role in higher brain function. We analysed the expression pattern of four brain-specific snoRNAs: MBI-36, MBII-48, MBII-52 and MBII-85, in mouse brain using in situ hybridization. All of these genes were expressed in the hippocampus and, except for MBII-85, their levels in ventral parts were higher than those in dorsal parts. Using quantitative real-time polymer chain reaction we determined hippocampal expression changes after contextual fear conditioning in mice. Ninety minutes, but not 25 h, after conditioning, we observed significant downregulation of MBII-48 and upregulation of MBII-52. Our finding that the expression of MBII-48 and MBII-52 is regulated during learning suggests that these snoRNAs have an important role in higher brain function.

Animals↗