HECTD2 Is Associated with Susceptibility to Mouse and Human Prion Disease

Lloyd, Sarah E.; Maytham, Emma G.; Pota, Hirva; Grizenkova, Julia; Molou, Eleni; Uphill, James; Hummerich, Holger; Whitfield, Jerome; Alpers, Michael P.; Mead, Simon; Collinge, John

doi:10.1371/journal.pgen.1000383

Cited by 67 publications

(61 citation statements)

References 36 publications

(41 reference statements)

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“…S4 A and B). HECTD2 is implicated in regulating PIAS1 (32) and as a candidate susceptibility gene in Alzheimer's disease and Creutzfeldt-Jakob disease (33,34). Consistent with the result of the siRNA screen, HECTD2 coimmunoprecipitates LCA but not LCE (Fig.…”

Section: Resultssupporting

confidence: 80%

Deubiquitinating enzyme VCIP135 dictates the duration of botulinum neurotoxin type A intoxication

Tsai

Kotiya

Kiris

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Significance Botulinum neurotoxins (BoNTs) are the most potent biological toxins. These proteases function by cleaving SNARE proteins, leading to paralysis and death from respiratory failure. BoNT serotype A (BoNT/A) has the most prolonged symptoms due to an extraordinarily stable catalytic light chain (LCA). BoNT/A intoxication can occur through ingestion (either sporadically or from a common food source), as a consequence of a clinical mishap, or potentially through bioterrorism, which would require mass mechanical ventilation. We report that LCA persistence is due to a particular deubiquitinating enzyme that binds a specific region of LCA and prevents its ubiquitin-dependent proteasomal degradation. These findings represent an essential step toward developing targeted molecular approaches to reducing morbidity and mortality from this toxin.

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Section: Resultssupporting

confidence: 80%

Deubiquitinating enzyme VCIP135 dictates the duration of botulinum neurotoxin type A intoxication

Tsai

Kotiya

Kiris

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Modelling cannot estimate the number of sub-clinically infected carriers, and the discrepancy between numbers of clinical cases and prevalence estimates from 512 JDF Wadsworth et al population screening remains unexplained [16][17][18][19]. Incubation periods in human prion infections, even in the absence of a species barrier, may exceed five decades [6,20,21], and multiple genetic loci in addition to the PrP gene are known to influence prion incubation periods in mice [22][23][24][25] and susceptibility in humans [26,27]. Asymptomatically infected carriers appear to have transmitted vCJD prion infection and disease to others via blood transfusion [28][29][30] or blood products [31].…”

Section: Introductionmentioning

confidence: 99%

Effect of fixation on brain and lymphoreticular vCJD prions and bioassay of key positive specimens from a retrospective vCJD prevalence study

Wadsworth

Dalmau-Mena

Joiner

et al. 2010

The Journal of Pathology

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Anonymous screening of lymphoreticular tissues removed during routine surgery has been applied to estimate the UK population prevalence of asymptomatic vCJD prion infection. The retrospective study of Hilton et al (J Pathol 2004; 203: 733-739) found accumulation of abnormal prion protein in three formalin-fixed appendix specimens. This led to an estimated UK prevalence of vCJD infection of ∼1 in 4000, which remains the key evidence supporting current risk reduction measures to reduce iatrogenic transmission of vCJD prions in the UK. Confirmatory testing of these positives has been hampered by the inability to perform immunoblotting of formalin-fixed tissue. Animal transmission studies offer the potential for 'gold standard' confirmatory testing but are limited by both transmission barrier effects and known effects of fixation on scrapie prion titre in experimental models. Here we report the effects of fixation on brain and lymphoreticular human vCJD prions and comparative bioassay of two of the three prevalence study formalin-fixed, paraffin-embedded (FFPE) appendix specimens using transgenic mice expressing human prion protein (PrP). While transgenic mice expressing human PrP 129M readily reported vCJD prion infection after inoculation with frozen vCJD brain or appendix, and also FFPE vCJD brain, no infectivity was detected in FFPE vCJD spleen. No prion transmission was observed from either of the FFPE appendix specimens. The absence of detectable infectivity in fixed, known positive vCJD lymphoreticular tissue precludes interpreting negative transmissions from vCJD prevalence study appendix specimens. In this context, the Hilton et al study should continue to inform risk assessment pending the outcome of larger-scale studies on discarded surgical tissues and autopsy samples.

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“…In mice, this is exemplified by the comparison of incubation times from a range of Prnp a inbred lines showing a difference of over 100 d between the shortest and longest incubation time strains (11). Many approaches have been taken to identify susceptibility genes including a genome-wide association study (GWAS) for variant CJD (vCJD) (6), and in mice, several studies have carried out quantitative trait loci mapping in both twoway crosses and a heterogeneous cross (12)(13)(14). In these studies, the underlying functional polymorphism is unknown but could be an amino acid change within the coding region of a protein or splicing variant or may occur within noncoding sequences such as untranslated regions, promoters, or other regulatory regions thereby influencing the pattern or level of expression.…”

mentioning

confidence: 99%

Overexpression of the Hspa13 ( Stch ) gene reduces prion disease incubation time in mice

Grizenkova

Akhtar

Hummerich

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Prion diseases are fatal neurodegenerative disorders that include bovine spongiform encephalopathy (BSE) and scrapie in animals and Creutzfeldt-Jakob disease (CJD) in humans. They are characterized by long incubation periods, variation in which is determined by many factors including genetic background. In some cases it is possible that incubation time may be directly correlated to the level of gene expression. To test this hypothesis, we combined incubation time data from five different inbred lines of mice with quantitative gene expression profiling in normal brains and identified five genes with expression levels that correlate with incubation time. One of these genes, Hspa13 (Stch), is a member of the Hsp70 family of ATPase heat shock proteins, which have been previously implicated in prion propagation. To test whether Hspa13 plays a causal role in determining the incubation period, we tested two overexpressing mouse models. The Tc1 human chromosome 21 (Hsa21) transchromosomic mouse model of Down syndrome is trisomic for many Hsa21 genes including Hspa13 and following Chandler/Rocky Mountain Laboratory (RML) prion inoculation, shows a 4% reduction in incubation time. Furthermore, a transgenic model with eightfold overexpression of mouse Hspa13 exhibited highly significant reductions in incubation time of 16, 15, and 7% following infection with Chandler/RML, ME7, and MRC2 prion strains, respectively. These data further implicate Hsp70-like molecular chaperones in protein misfolding disorders such as prion disease.

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HECTD2 Is Associated with Susceptibility to Mouse and Human Prion Disease

Cited by 67 publications

References 36 publications

Deubiquitinating enzyme VCIP135 dictates the duration of botulinum neurotoxin type A intoxication

Deubiquitinating enzyme VCIP135 dictates the duration of botulinum neurotoxin type A intoxication

Effect of fixation on brain and lymphoreticular vCJD prions and bioassay of key positive specimens from a retrospective vCJD prevalence study

Overexpression of the Hspa13 ( Stch ) gene reduces prion disease incubation time in mice

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