Genes implicated in multiple sclerosis pathogenesis from consilience of genotyping and expression profiles in relapse and remission

<p>Abstract</p> <p>Background</p> <p>Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Although the pathogenesis of MS remains unknown, it is widely regarded as an autoimmune disease mediated by T-lymphocytes directed against myelin proteins and/or other oligodendrocyte epitopes.</p> <p>Methods</p> <p>In this study we investigated the gene expression profiles of peripheral blood cells from patients with RRMS during the relapse and the remission phases utilizing gene microarray technology. Dysregulated genes encoded in regions associated with MS susceptibility from genomic screens or previous trancriptomic studies were identified. The proximal promoter region polymorphisms of two genes were tested for association with disease and expression level.</p> <p>Results</p> <p>Distinct sets of dysregulated genes during the relapse and remission phases were identified including genes involved in apoptosis and inflammation. Three of these dysregulated genes have been previously implicated with MS susceptibility in genomic screens: TGFβ1, CD58 and DBC1. TGFβ1 has one common SNP in the proximal promoter: -508 T>C (rs1800469). Genotyping two Australian trio sets (total 620 families) found a trend for over-transmission of the T allele in MS in females (p < 0.13). Upregulation of CD58 and DBC1 in remission is consistent with their putative roles in promoting regulatory T cells and reducing cell proliferation, respectively. A fourth gene, ALOX5, is consistently found over-expressed in MS. Two common genetic variants were confirmed in the ALOX5 putatve promoter: -557 T>C (rs12762303) and a 6 bp tandem repeat polymorphism (GGGCGG) between position -147 and -176; but no evidence for transmission distortion found.</p> <p>Conclusion</p> <p>The dysregulation of these genes tags their metabolic pathways for further investigation for potential therapeutic intervention.</p

Protein kinase C modulation of thermo-sensitive transient receptor potential channels: Implications for pain signaling

A variety of molecules are reported to be involved in chronic pain. This review outlines the specifics of protein kinase C (PKC), its isoforms and their role in modulating thermo-sensitive transient receptor potential (TRP) channels TRPV1-4, TRPM8, and TRPA1. Anatomically, PKC and thermo-sensitive TRPs are co-expressed in cell bodies of nociceptive dorsal root ganglion (DRG) neurons, which are used as physiological correlates of peripheral and central projections involved in pain transmission. In the past decade, modulation of painful heat-sensitive TRPV1 by PKC has received the most attention. Recently, PKC modulation of other newly discovered thermo-sensitive pain-mediating TRPs has come into focus. Such modulation may occur under conditions of chronic pain resulting from nerve damage or inflammation. Since thermo-TRPs are primary detectors of acute pain stimuli, their modulation by PKC can severely alter their function, resulting in chronic pain. Comprehensive knowledge of pain signaling involving interaction of specific isoforms of PKC with specific thermo-sensitive TRP channels is incomplete. Such information is necessary to dissect out modality specific mechanisms to better manage the complex polymodal nature of chronic pain. This review is an attempt to update the readers on current knowledge of PKC modulation of thermo-sensitive TRPs and highlight implications of such modulation for pain signalin

Herpes Simplex Virus Tegument Protein US11 Interacts with Conventional Kinesin Heavy Chain

Little is known about the mechanisms of transport of neurotropic herpesviruses, such as herpes simplex virus (HSV), varicella-zoster virus, and pseudorabies virus, within neurons. For these viruses, which replicate in the nucleus, anterograde transport from the cell body of dorsal root ganglion (DRG) neurons to the axon terminus occurs over long distances. In the case of HSV, unenveloped nucleocapsids in human DRG neurons cocultured with autologous skin were observed by immunoelectron microscopy to colocalize with conventional ubiquitous kinesin, a microtubule-dependent motor protein, in the cell body and axon during anterograde axonal transport. Subsequently, four candidate kinesin-binding structural HSV proteins were identified (VP5, VP16, VP22, and US11) using oligohistidine-tagged human ubiquitous kinesin heavy chain (uKHC) as bait. Of these viral proteins, a direct interaction between uKHC and US11 was identified. In vitro studies identified residues 867 to 894 as the US11-binding site in uKHC located within the proposed heptad repeat cargo-binding domain of uKHC. In addition, the uKHC-binding site in US11 maps to the C-terminal RNA-binding domain. US11 is consistently cotransported with kinetics similar to those of the capsid protein VP5 into the axons of dissociated rat neurons, unlike the other tegument proteins VP16 and VP22. These observations suggest a major role for the uKHC-US11 interaction in anterograde transport of unenveloped HSV nucleocapsids in axons