Term
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Definition
| proteinaceous infectious particles - which aggregate over time, forming conformations which are difficult to break down once they have formed. |
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Term
| what was the first documentation of prion disease in humans? |
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Definition
| creutzfeldt-jacob disease in 1921. symptoms: dementia, gait problems, ataxia, speech issues were evident. this term is still used for most prion disease except that derived from beef. |
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Term
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Definition
| a transmissible spongiform encephalopathy due to cannibalism first described in 1950's papua new guinea |
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Term
| when was the connection between prion disease and proteins made? |
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Definition
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Term
| where do prions come from? what are the different forms? |
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Definition
| they are encoded by chr 20, which codes for a 250 AA, membrane associated, glycosylated, synaptic membrane protein of neurons (can help schwann cells myelinate neurons). *PrPc = nonpathogenic cellular form. *PrPSc = pathogenic form - aggregates to form rod-like particles (brain homogenates of PrPSc cause disease upon injection). |
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Term
| what characterizes the aggregates formed by prions? |
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Definition
| they form aggregates w/a high degree of beta pleated sheet conformation - makes them very difficult to digest by proteases. 10% form amyloid plaques which simply describes non specific protein accumulation (different than amyloid beta plaques seen in alzheimer's). |
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Term
| what characterizes the PrPc prion form? |
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Definition
| 45% alpha helix, no beta sheet. protease sensitive. soluble in nondenaturing agents. |
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Term
| what characterizes the PrPSc prion form? |
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Definition
| 30% alpha helix, 45% beta sheet. protease resistant. insoluble in nondenaturing agents. |
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Term
| how was prion disease determined to be different than that due to a virus? |
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Definition
| agents which work against proteins (denaturing agents) affected PrPSc, but had no effect on viruses. enzymatic tx using DNAase/RNAase had no effect on prions, but did on viruses. determined that the scrapie prion is different than a virus. |
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Term
| what does it mean to say prions are well conserved w/in animal populations? |
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Definition
| each species makes its own conformation of prion. the BSE (bovine spongiform encephalopathy) prion has high homology to the human form - meaning it can cause human disease (new variant CJD). |
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Term
| can there be a genetic predisposition for developing prion disease? |
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Definition
| yes, but this is rare. usually due to inherited point mutations or possibly somatic mutations. |
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Term
| what does it mean that prions are resistant to UV radiation? |
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Definition
| this is a good sign that only a protein is involved. |
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Term
| is synthetically produced mutant PrP which contains beta sheet structure and is protease resistance infectious? |
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Definition
| no, this implies a possible chaperone. PrPSc induces a conformational change in PrPc likely using a species specific RNA or some other substance (has been replicated in lab). RNA levels of a specific kind (that for the erythroid differentiation related factor - EDRF) have found to be lower in BSE-infected animals = EDRF may be a good diagnostic marker. |
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Term
| can PrPSc interact w/normal cells? |
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Definition
| yes - it converts normal protein to an abnormal structure which has a high beta pleated sheet conformation (protease resistant). this aggregation eventually kills the cell which is eventually resorbed. astrocytes then wall these areas of resorption off = spongy tissue appearance. **there is not a massive inflammatory response. |
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Term
| what happens if you block (normal) PrPc in a cell (via inhibition of microRNAs)? |
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Definition
| this doesn't seem to affect the body *other than rendering it immune to the effects of PrPSc |
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Term
| what are the animal forms of prion disease? |
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Definition
| scrapie: sheep infected from pasture w/placental tissue carrying the agent?. BSE: due to bone meal from sheep offal for cattle feed. if humans eat the affected sheep they will not get disease, but if they eat cows which ate the sheep = humans will get the disease. |
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Term
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Definition
| brains from people in papau new guinea were found to resemble CJD after they ate CNS parts of dead tribe members. sometimes the disease would present several decades later. |
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Term
| is disease due to prions inflammatory? |
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Definition
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Term
| what are the 4 types of CJD? |
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Definition
| iatrogenic, familial, sporadic, and new variant. |
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Term
| what characterizes iatrogenic CJD? |
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Definition
| accidental transmission from corneal transplants, contaminated EEG electrodes/sx instruments, dura mater grafts, GH and human gonadotropin (pituitary gland harbors prions). bleach not autoclaving will decontaminate prions. |
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Term
| what characterizes familial CJD? |
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Definition
| this is due to point mutations on chr 20 and only accounts for ~10% of CJD. |
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Term
| what characterizes sporadic CJD? |
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Definition
| this is due to: spontaneous conversion of PrPc -> PrPSc, an environmental insult = somatic mutation, or prions transmitted from an animal. 300 cases in the US. if pts are homozygous in the gene for prion protein which codes for methionine or valine at a particular codon it will increase CJD risk. thought to target the lymphoreticular system (then taken to the nervous system), however PrPSc has been found in muscle tissue as well. |
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Term
| what characterizes new variant CJD? |
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Definition
| this characterizes disease seen in pts who ate beef infected w/BSE. pts were 17-55 y/o, developed late dementia, PrPSc plaques resembled those seen in kuru, but there was **absence of EEG features seen in typical CJD. BSE prions when injected into mice: could get the disease and then extract out the abnormal prions and their conformation was consistent with what was found with BSE cow brain (proven transmissible). |
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Term
| what characterizes the link between CJD and alzheimer's? |
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Definition
| one study found 3-5% of those diagnosed with AD actually had CJD |
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Term
| what is important about chronic wasting disease of elk? |
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Definition
| it was shown that *muscle tissue* from elk w/chronic wasting disease (CJD variant) could infect mice and cause them to produce the same abnormal prions (unknown if this will lead to full-blown CJD). |
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Term
| what is gerstmann-straussler-scheinker disease (GSS)? |
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Definition
| an inherited form of prion disease which shows up in the 4-5th decade. initial symptoms: cerebellar ataxia/motor problems. |
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Term
| what is fatal familial insomnia? |
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Definition
| pts have inability to sleep and dysautonomia - due to severe selective atrophy of the thalamus. |
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Term
| what characterizes incidence of CJD? |
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Definition
| 1/1,000,000. usually pts are 40-70 y/o. |
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Term
| what characterizes the pathology due to CJD? |
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Definition
| **non-inflammatory lesions, vacuoles (spongiform degeneration of neurons), astrogliosis, neuronal loss, and ~10% have amyloid plaques containing PrPSc |
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Term
| which cells are thought to take up prion proteins? |
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Definition
| the follicular dendritic cells (in spleen, peyer's patches). this suggests that inflammation and/or infections should reduce the distance between the FDCs and the nerves - facilitating prion disease susceptibility. FDCs positioned naturally close to sympathetic nerves may hasten neuroinvasion. |
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Term
| what are diagnostics for prion disease? |
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Definition
| based on exam of brain tissue, some cases have characteristic EEGs, PrPSc detected immunologically from brain homogenates, prenatal screening for some inherited types, and bioassay (put sample tissue in mouse - takes at least a year). also: Ab testing, histochemistry, western blots, and ELISA. |
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Term
| can PrPSc be transmitted through blood transfusion? |
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Definition
| yes. but leukoreduction can be used to get rid of WBCs - lowers risk of transmission. |
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Term
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Definition
| nothing yet. tetracycline might inactivate PrPSc. acridine, phenothiazine and psychotropic drugs might stabilize PrPc. |
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