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Friday Science Review: October 14, 2011

Ubiquitin Ligase Sweeps Aggregates

University of British Columbia ♦ Published in Nature Cell Biology, October 9, 2011

It seems that ubiquitin ligase may play a critical role in preventing diseases characterized by protein aggregation. The enzyme acts by fusing a polyubiquitin chain to misfolded proteins that sit in the cytoplasm. Once tagged, these faulty proteins are degraded by other enzymes in the proteasome. Researchers at the University of British Columbia utilized heat-shock to create short-term stores of misfolded proteins in yeast cells and demonstrated that a specific ubiquitin ligase, Hul5, is responsible for ubiquitylation and removal of low-solubility proteins. Pin2, a protein involved in the development of prion disease, was also observed to be removed by Hul5.

Key Determinant of Osteoporosis Discovered

University of Montreal ♦ McGill University ♦ Laval University ♦ Washington University School of Medicine

Published in Cell Metabolism, October 5, 2011

Researchers have discovered a factor that controls the differentiation of osteoclasts, the cell type responsible for bone resorption. Bone resorption is one of two processes that act in concert to ensure a constant bone mass in the human body. When this balance is broken the result is loss of bone density, otherwise known as osteoporosis. When resorption occurs osteoclasts break down releasing calcium into the bloodstream which in turn regulates bone formation. Inppb4α seems to regulate osteoclastogenesis by repressing the differentiation of osteoclasts. Mice deficient in Inppb4α exhibit accelerated osteoclast differentiation and bone loss. An important finding in this study was that the human gene, INPP4B, was found to be a susceptibility locus for osteoporosis, confirming the functional analysis carried out in mice.

Antisense Oligos for Huntington Disease

University of British Columbia ♦ Isis Pharmaceuticals ♦ University of Copenhagen

Published in Molecular Therapy, October 4, 2011

Huntington disease (HD) is characterized by a CAG nucleotide expansion in the Huntington gene (HTT). Hence, targeting the HTT gene has been a desirable therapeutic approach. However, the wild-type (normal and healthy) HTT gene is crucial for neuronal development and survival so down regulating its expression can have deleterious effects. To circumvent this researchers created gene-silencing antisense oligonucleotides (ASOs) that target small variable regions known as single nucleotide polymorphisms (SNPs) found in the HD population. ASOs were modified with S-constrained ethyl (cET) motifs to ensure selectivity of target sites. Delivery of ASOs to the mouse brain demonstrated allele-specific knockdown of the HTT protein in vivo.

Optimizing Lipid Nanoparticles for Delivery of Therapeutic Payload

University of British Columbia ♦ Published in Molecular Therapy, October 4, 2011

One of the most effective means to deliver therapeutic payloads is to drop them into lipid nanoparticles (LNPs) for in vivo delivery. LNPs are easier to manufacture than viral vectors and have lower immunogenicity, making LNP delivery systems an attractive option. In this study researchers investigated the potency of RNAi on primary bone macrophages and dendritic cells using any one of four cationic lipids to build LNPs. Of the four lipids used, DLinkC2-DMA provided the most potent intracellular delivery in vitro and in vivo. To demonstrate the efficacy of DLinkC2-DMA-containing LNPs researchers loaded them with GAPDH-siRNA and administered them intravenously to mice. Significant inhibition of GAPDH and CD45 was observed in spleen and peritoneal macrophages and dendritic cells in relation to LNPs containing other lipid types.

Long Non-Coding RNAs, Dark Matter Comes into Light

British Columbia Cancer Agency Research Centre ♦ University of British Columbia

Published in PLoS ONE, October 3, 2011

Researchers have had a change of heart with respect to the contribution that long non-coding RNAs (LncRNAs) have to cancer formation. LncRNAs do not code for proteins, instead serving structural and functional roles in the cell. Due to the fact that they are not actually translated to proteins, LncRNAs have been dubbed the ‘dark matter’ of the transcriptome. Conservative estimates put their numbers somewhere in the vicinity of 23,000 transcripts. LncRNAs have been implicated in at least two cancer types, breast cancer and lung cancer, but this paper is the first large scale analysis of their contribution to human cancers. By comparing 26 different normal human tissues and 19 human cancers, researchers show that in many cancers LncRNAs are aberrantly expressed and may not be as innocuous as most think. Today’s current commercial microarrays used for transcriptome profiling focus on coding regions of the transcriptome. We may now have to place more emphasis on non-coding regions in order to capture a more comprehensive view of how the transcriptome can contribute to the development of cancer.

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