The Prion Disease Database: a comprehensive transcriptome resource for systems biology research in prion diseases

Gehlenborg, Nils; Hwang, Daehee; Lee, Inyoul Y.; Yoo, Hyuntae; Baxter, David; Petritis, Brianne; Pitstick, Rose; Marzolf, Bruz; DeArmond, Stephen J.; Carlson, George A.; Hood, Leroy

doi:10.1093/database/bap011

Cited by 18 publications

(28 citation statements)

References 27 publications

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“…This finding was verified using microarray analysis of various mouse genetic background/prion strain combinations over the entire incubation period [23], [36]. However, expression of Sprn mRNA - which is located on a different chromosome from Prnp (chr 7 versus chr 2) [37]-might be quite different.…”

Section: Resultsmentioning

confidence: 71%

Down-Regulation of Shadoo in Prion Infections Traces a Pre-Clinical Event Inversely Related to PrPSc Accumulation

et al. 2011

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During prion infections of the central nervous system (CNS) the cellular prion protein, PrPC, is templated to a conformationally distinct form, PrPSc. Recent studies have demonstrated that the Sprn gene encodes a GPI-linked glycoprotein Shadoo (Sho), which localizes to a similar membrane environment as PrPC and is reduced in the brains of rodents with terminal prion disease. Here, analyses of prion-infected mice revealed that down-regulation of Sho protein was not related to Sprn mRNA abundance at any stage in prion infection. Down-regulation was robust upon propagation of a variety of prion strains in Prnp a and Prnp b mice, with the exception of the mouse-adapted BSE strain 301 V. In addition, Sho encoded by a TgSprn transgene was down-regulated to the same extent as endogenous Sho. Reduced Sho levels were not seen in a tauopathy, in chemically induced spongiform degeneration or in transgenic mice expressing the extracellular ADan amyloid peptide of familial Danish dementia. Insofar as prion-infected Prnp hemizygous mice exhibited accumulation of PrPSc and down-regulation of Sho hundreds of days prior to onset of neurologic symptoms, Sho depletion can be excluded as an important trigger for clinical disease or as a simple consequence of neuronal damage. These studies instead define a disease-specific effect, and we hypothesize that membrane-associated Sho comprises a bystander substrate for processes degrading PrPSc. Thus, while protease-resistant PrP detected by in vitro digestion allows post mortem diagnosis, decreased levels of endogenous Sho may trace an early response to PrPSc accumulation that operates in the CNS in vivo. This cellular response may offer new insights into the homeostatic mechanisms involved in detection and clearance of the misfolded proteins that drive prion disease pathogenesis.

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Section: Resultsmentioning

confidence: 71%

Down-Regulation of Shadoo in Prion Infections Traces a Pre-Clinical Event Inversely Related to PrPSc Accumulation

et al. 2011

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“…Microarray-based dynamic gene expression profiles during prion disease development in different combinations of mouse strains and prion strains were obtained through the Prion Disease DataBase (PDDB) [ 25 , 26 ], through the following website: http://prion.systemsbiology.net/page/Welcome/display .…”

Section: Methodsmentioning

confidence: 99%

Prion Pathogenesis in the Absence of NLRP3/ASC Inflammasomes

2015

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The accumulation of the scrapie prion protein PrPSc, a misfolded conformer of the cellular prion protein PrPC, is a crucial feature of prion diseases. In the central nervous system, this process is accompanied by conspicuous microglia activation. The NLRP3 inflammasome is a multi-molecular complex which can sense heterogeneous pathogen-associated molecular patterns and culminates in the activation of caspase 1 and release of IL 1β. The NLRP3 inflammasome was reported to be essential for IL 1β release after in vitro exposure to the amyloidogenic peptide PrP106-126 and to recombinant PrP fibrils. We therefore studied the role of the NLRP3 inflammasome in a mouse model of prion infection. Upon intracerebral inoculation with scrapie prions (strain RML), mice lacking NLRP3 (Nlrp3-/-) or the inflammasome adaptor protein ASC (Pycard-/-) succumbed to scrapie with attack rates and incubation times similar to wild-type mice, and developed the classic histologic and biochemical features of prion diseases. Genetic ablation of NLRP3 or ASC did not significantly impact on brain levels of IL 1β at the terminal stage of disease. Our results exclude a significant role for NLRP3 and ASC in prion pathogenesis and invalidate their claimed potential as therapeutic target against prion diseases.

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“…Although Padi2 expression differed significantly, it was down-regulated in the microarray data but up-regulated in the qRT-PCR analysis. A search of the Prion Disease Database indicates that very few of these genes nor Sox10 itself were significantly perturbed in prion disease (Gehlenborg et al 2009; Hwang et al 2009). SOX10 loss-of-function and prions both appear to disrupt cholesterol metabolism and sterol biosynthesis processes, however (Table 2 and Cui et al 2014; Kumar et al 2008), suggesting there may be some shared pathways that contribute to CNS vacuolation.…”

Section: Resultsmentioning

confidence: 99%

Disrupted SOX10 function causes spongiform neurodegeneration in gray tremor mice

et al. 2014

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Mice homozygous for the gray tremor (gt) mutation have a pleiotropic phenotype that includes pigmentation defects, megacolon, whole body tremors, sporadic seizures, hypo- and dysmyelination of the CNS and PNS, vacuolation of the CNS, and early death. Vacuolation similar to that caused by prions was originally reported to be transmissible, but subsequent studies showed the inherited disease was not infectious. The gt mutation mapped to distal mouse chromosome 15, to the same region as Sox10, which encodes a transcription factor with essential roles in neural crest survival and differentiation. As dominant mutations in mouse or human SOX10 cause white spotting and intestinal aganglionosis, we screened the Sox10 coding region for mutations in gt/gt DNA. An adenosine to guanine transversion was identified in exon 2 that changes a highly conserved glutamic acid residue in the SOX10 DNA binding domain to glycine. This mutant allele was not seen in wildtype mice, including the related GT/Le strain, and failed to complement a Sox10 null allele. Gene expression analysis revealed significant down-regulation of genes involved in myelin lipid biosynthesis pathways in gt/gt brains. Knockout mice for some of these genes develop CNS vacuolation and/or myelination defects, suggesting that their down-regulation may contribute to these phenotypes in gt mutants and could underlie the neurological phenotypes associated with Peripheral demyelinating neuropathy-Central dysmyelinating leukodystrophy-Waardenburg syndrome-Hirschsprung (PCWH) disease, caused by mutations in human SOX10.

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The Prion Disease Database: a comprehensive transcriptome resource for systems biology research in prion diseases

Cited by 18 publications

References 27 publications

Down-Regulation of Shadoo in Prion Infections Traces a Pre-Clinical Event Inversely Related to PrPSc Accumulation

Down-Regulation of Shadoo in Prion Infections Traces a Pre-Clinical Event Inversely Related to PrPSc Accumulation

Prion Pathogenesis in the Absence of NLRP3/ASC Inflammasomes

Disrupted SOX10 function causes spongiform neurodegeneration in gray tremor mice

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