370 research outputs found
Lattice congruences of the weak order
We study the congruence lattice of the poset of regions of a hyperplane
arrangement, with particular emphasis on the weak order on a finite Coxeter
group. Our starting point is a theorem from a previous paper which gives a
geometric description of the poset of join-irreducibles of the congruence
lattice of the poset of regions in terms of certain polyhedral decompositions
of the hyperplanes. For a finite Coxeter system (W,S) and a subset K of S, let
\eta_K:w \mapsto w_K be the projection onto the parabolic subgroup W_K. We show
that the fibers of \eta_K constitute the smallest lattice congruence with
1\equiv s for every s\in(S-K). We give an algorithm for determining the
congruence lattice of the weak order for any finite Coxeter group and for a
finite Coxeter group of type A or B we define a directed graph on subsets or
signed subsets such that the transitive closure of the directed graph is the
poset of join-irreducibles of the congruence lattice of the weak order.Comment: 26 pages, 4 figure
NF-κB Mediates Tumor Necrosis Factor α-Induced Expression of Optineurin, a Negative Regulator of NF-κB
Optineurin is a ubiquitously expressed multifunctional cytoplasmic protein encoded by OPTN gene. The expression of optineurin is induced by various cytokines. Here we have investigated the molecular mechanisms which regulate optineurin gene expression and the relationship between optineurin and nuclear factor κB (NF-κB). We cloned and characterized human optineurin promoter. Optineurin promoter was activated upon treatment of HeLa and A549 cells with tumor necrosis factor α (TNFα). Mutation of a putative NF-κB-binding site present in the core promoter resulted in loss of basal as well as TNFα-induced activity. Overexpression of p65 subunit of NF-κB activated this promoter through NF-κB site. Oligonucleotides corresponding to this putative NF-κB-binding site showed binding to NF-κB. TNFα-induced optineurin promoter activity was inhibited by expression of inhibitor of NF-κB (IκBα) super-repressor. Blocking of NF-κB activation resulted in inhibition of TNFα-induced optineurin gene expression. Overexpressed optineurin partly inhibited TNFα-induced NF-κB activation in Hela cells. Downregulation of optineurin by shRNA resulted in an increase in TNFα-induced as well as basal NF-κB activity. These results show that optineurin promoter activity and gene expression are regulated by NF-κB pathway in response to TNFα. In addition these results suggest that there is a negative feedback loop in which TNFα-induced NF-κB activity mediates expression of optineurin, which itself functions as a negative regulator of NF-κB
Significance of the parkin and PINK1 gene in Jordanian families with incidences of young-onset and juvenile parkinsonism
<p>Abstract</p> <p>Background</p> <p>Parkinson's disease is a progressive neurodegenerative disorder, where most cases are sporadic with a late onset. In rare incidences familial forms of early-onset parkinsonism occur, and when recessively inherited, cases are often explained by mutations in either the <it>parkin </it>(PARK2) or <it>PINK1 </it>(PARK6) gene or on exceptional occasions the <it>DJ-1 </it>(PARK7) or <it>ATP13A2 </it>(PARK9) gene. Recessively inherited deletions/duplications and point mutations in the <it>parkin </it>gene are the most common cause of early-onset parkinsonism known so far, but in an increasing number of studies, genetic variations in the serine/threonine kinase domain of the <it>PINK1 </it>gene are found to explain early-onset parkinsonism.</p> <p>Methods</p> <p>In this study all families were from a population with a high incidence of consanguinity. We investigated 11 consanguineous families comprising 17 affected with recessively inherited young-onset parkinsonism for mutations both in the <it>parkin </it>and <it>PINK1 </it>gene. Exons and flanking regions were sequenced, and segregation patterns of genetic variation were assessed in members of the respective families. An exon dosage analysis was performed for all exons in both genes.</p> <p>Results</p> <p>In the <it>parkin </it>gene, a three generation family was identified with an exon 4 deletion segregating with disease. Both affected were homozygous for the deletion that segregated on a haplotype that spanned the gene in a haplotype segregation analysis that was performed using additional markers. Exon dosage analysis confirmed the recessive pattern of inheritance with heterozygous deletions segregating in healthy family members. In the <it>PINK1 </it>gene we identified two novel putative pathogenic substitutions, P416R and S419P, located in a conserved motif of the serine/threonine kinase domain. Both substitutions segregated with disease in agreement with a recessive pattern of inheritance within respective families and both were present as homozygous in two affected each. We also discuss common polymorphisms in the two genes found to be co-segregating within families.</p> <p>Conclusion</p> <p>Our results further extend on the involvement of <it>PINK1 </it>mutations in recessive early-onset parkinsonism with clinical features similar to carriers of <it>parkin </it>mutations.</p
A linkage study of candidate loci in familial Parkinson's Disease
BACKGROUND: Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease. Most cases are sporadic, however familial cases do exist. We examined 12 families with familial Parkinson's disease ascertained at the Movement Disorder clinic at the Oregon Health Sciences University for genetic linkage to a number of candidate loci. These loci have been implicated in familial Parkinson's disease or in syndromes with a clinical presentation that overlaps with parkinsonism, as well as potentially in the pathogenesis of the disease. METHODS: The examined loci were PARK3, Parkin, DRD (dopa-responsive dystonia), FET1 (familial essential tremor), BDNF (brain-derived neurotrophic factor), GDNF (glial cell line-derived neurotrophic factor), Ret, DAT1 (the dopamine transporter), Nurr1 and Synphilin-1. Linkage to the α-synuclein gene and the Frontotemporal dementia with parkinsonism locus on chromosome 17 had previously been excluded in the families included in this study. Using Fastlink, Genehunter and Simwalk both parametric and model-free non-parametric linkage analyses were performed. RESULTS: In the multipoint parametric linkage analysis lod scores were below -2 for all loci except FET1 and Synphilin-1 under an autosomal dominant model with incomplete penetrance. Using non-parametric linkage analysis there was no evidence for linkage, although linkage could not be excluded. A few families showed positive parametric and non-parametric lod scores indicating possible genetic heterogeneity between families, although these scores did not reach any degree of statistical significance. CONCLUSIONS: We conclude that in these families there was no evidence for linkage to any of the loci tested, although we were unable to exclude linkage with both parametric and non-parametric methods
Is inhibition of kinase activity the only therapeutic strategy for LRRK2-associated Parkinson's disease?
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are a common cause of familial Parkinson's disease (PD). Variation around the LRRK2 locus also contributes to the risk of sporadic PD. The LRRK2 protein contains a central catalytic region, and pathogenic mutations cluster in the Ras of complex protein C terminus of Ras of complex protein (mutations N1437H, R1441G/C and Y1699C) and kinase (G2019S and I2020T) domains. Much attention has been focused on the kinase domain, because kinase-dead versions of mutant LRRK2 are less toxic than kinase-active versions of the same proteins. Furthermore, kinase inhibitors may be able to mimic this effect in mouse models, although the currently tested inhibitors are not completely specific. In this review, we discuss the recent progress in the development of specific LRRK2 kinase inhibitors. We also discuss non-kinase-based therapeutic strategies for LRRK2-associated PD as it is possible that different approaches may be needed for different mutations
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LRRK2 at the interface of autophagosomes, endosomes and lysosomes
Over the past 20 years, substantial progress has been made in identifying the underlying genetics of Parkinson’s disease (PD). Of the known genes, LRRK2 is a major genetic contributor to PD. However, the exact function of LRRK2 remains to be elucidated. In this review, we discuss how familial forms of PD have led us to hypothesize that alterations in endomembrane trafficking play a role in the pathobiology of PD. We will discuss the major observations that have been made to elucidate the role of LRRK2 in particular, including LRRK2 animal models and high-throughput proteomics approaches. Taken together, these studies strongly support a role of LRRK2 in vesicular dynamics. We also propose that targeting these pathways may not only be beneficial for developing therapeutics for LRRK2-driven PD, but also for other familial and sporadic cases
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