PATH 310 Final Exam
What was HD referred to as by natives?
"that disorder"
Describe direct HPV testing for screening in Ontario
-$100 -may become government funded shortly
How many types of HPV are considered low risk? Why?
-12 -seldom the cause of cervical cancer
How many types of HPV are considered high risk? Why?
-15 -associated with cervical cancer
What are the types of HPV mainly responsible for cervical cancers? What percentage?
-16,18 -70% of cancers
When was the chromosomal location of the Huntington disease gene first found? Where was it?
-1983 -Chr 4 -predicted it would take 10 years to find the gene
When was the HD gene further localized? Where?
-1987 -Near the tip of the short arm of Chr 4 -flanked by D4S10 and the telomere
When was the HD gene found? Explain it
-1993 -located on Chr 4p16.3 -gene was IT15 (Huntingtin gene) -contained a trinucleotide repeat that was expanded and unstable on HD chromosomes -repeats located in the coding sequence -protein is widely expressed
How many early and late HPV proteins are there?
-6 early (there is NO E3) -2 late
What are the types of HPV mainly responsible for genital warts? What percentage?
-6,11 -90% of genital warts
How much of the population has been exposed to HPV at some point? How was this found?
-75% -Serology for HPV
What is the next step in HPV vaccination?
-9 valent -includes types 31, 33, 45, 52, 58 -from the makers of the quadravalent vaccine (Merck) -found to be equivalent to the quadravalent vaccine
What proportion of cervical cancer is due to HPV?
-99% -other sources are incredibly rare
What is a method being explored to silence the huntingtin gene?
-ASO -an allele specific oligonuclease -hybridizes to the expansion and causes the transcript to be degraded
How can a gene be silenced?
-ASO -smiRNA -shRNA -siRNA
What is a disease that has prion-like features? What makes it different
-Alzheimers -Not infectious like prions
When is there a significance rise in HPV prevalence?
-Around the age of onset of sexual activity -Declines with age
What is ASCUS?
-Atypical squamous cells of undetermined significance -worried about an LSIL, but cannot quite diagnose it -cannot guarantee that HPV is present
What pattern of inheritance does HD display?
-Autosomal dominant -Children with an affected parent have a 50% chance of inheriting the disease
What does EEG of sCJD show?
-Bilateral periodic discharges (approximately 1 per second) -very low amplitude, featureless background between complexes
What are some other potential treatment strategies for HD?
-Boosting natural defences -Increasing mitochondrial function -Interfere with protein misfolding -Intrabody generation -Removal or prevention of aggregate -Silencing of the gene
What models evolved for HD after the gene was identified? What are the positives and negatives
-C. elegans and D. melanogaster -Positives is that they are easy to manipulate genetically -Negatives are that it does not look like the human disease, have a fast life span, no blood brain barrier
What is the repeat that is expanded in the Huntingtin gene? Where is it located in the gene?
-CAG -encodes glutamine (causing a polyglutamine repeat) -located in the first exon
What can the targets be for ASO to treat HD?
-CAG repeat (oligo that only binds to the expanded allele) -a nearby heterozygous SNP
What classifications of cervical cells can be determined by histology?
-CIN1 -CIN2 -CIN3
Describe CIN
-Cervical intraepithelial neoplasia -not yet cancer -usually cureable
Describe the progression of signs/symptoms of HD
-Change in personality -Unreliable at work, difficulty multi-tasking -Increasing forgetfulness, restlessness and fidgeting -Clumsiness and awkward movements -Onset of chorea and motor coordination
What are some cytoplasmic effects of HD?
-Chaperone dysfunction (misfolding) -proteosome impairment -proteolytic cleavage -Cytoplasmic sequestration and aggregation (leads to inclusions, mitochondrial toxicity, vesicle transport dysfunction)
Who was mostly affected by Kuru? Why?
-Children and females -Due to the practice of eating brains of the deceased
What is another name for HD? How was this derived?
-Chorea -Greek for dance
What is the most visible symptom of HD?
-Chorea (uncontrolled movement) -Most often targeted for treatment
What is a treatment for HD used if the symptoms are not severe enough to impair function?
-Coenzyme Q and creatine
What is used as a treatment for HD to increase mitochondrial function?
-Coenzyme Q10 -acts as an electron acceptor in the ETC -also an antioxidant
What are the name of the trials for creatine in HD?
-Creatine safety, tolerability, and efficicacy in HD (CREST-E) -Creatine safety and tolerability in premanifest HD (PRECREST)
How can natural defences be boosted to combat HD?
-Creatine supports additional energy production in neurons that are dying -Highly unsaturated fatty acids can increase the ability of dying cells to maintain their integrity
What are the treatment options for HSIL/carcinoma?
-Cryotherapy -LEEP (loop electrosurgical excision procedure) -Cold knife cone biopsy
What are other diseases with CAG repeats (polyQ)
-DRPLA (denatotorubral-palidoluysian atrophy) -BCMA (spinobulbular muscular atrophy/ Kennedy disease) -SCA (spinocerebrellar ataxia)
What are some surgical interventions for HD?
-Deep brain stimulation -fetal cell transplantation
What is a side effect of tetrabenazine? Why is the particularly a problem for HD?
-Depression and sedation -Another symptom of HD is psychological issues, tetrabenazine increases these
What is a treatment for chorea in HD?
-Dopamine depletion (Tetrabenazine) -one of the few FDA approved drugs for treatment of chorea
How does HPV evade the immune response?
-E6 and E7 implicated in inhibition of TLR9 (dsDNA) gene transcription -down regulates interferon regulatory genes and upregulates TGF-B -does not elicit danger signals -E5 inhibits acification of endosomes and down-regulates MHC class I expression (major impact on immune recognition and NK cells) -increased viral protein expression only occurs in keratinocytes
List some trinuceotide expansion diseases
-Fragile X Syndrome -Friedreich ataxia -HD, Cerebral ataxia -Myotonic Dystrophy
What are some genetic disorders that display genetic anticipation?
-Fragile X syndrome -Myotonic dystrophy -Spinocerebellar ataxias
List the HPV-related diseases in order of decreasing prevalence
-Genital warts -Low grade cervical dysplasia -High grade cervical dysplasia -Cervical cancer -Head and neck cancer -Anal cancer -Vulvar and vaginal cancer -Penile cancer
What are some causes of sporadic CJD?
-HGH injection -dura mater grafts -packed red cell transfusion -corneal grafts -stereotactic surgery
What are the risk factors for cervical cancer?
-HPV infection -lack of effective screening -external factors are minor
Describe the progression of HPV infection
-HPV infection, koilocytosis -CIN1 (mild dysplasia) -CIN2 (Moderate dysplasia) -CIN3 (Severe dysplasia, carcinoma) -Invasive carcinoma
How was the initial link between sex and cervical cancer noted?
-Higher incidence of cervical cancer in married women, widows and prostitutes -rare occurrence in virgins and nuns
How can HD be prevented in transgenic mice?
-If the caspase-6 proteolytic cleavage site in huntingtin is eliminated -prevents the mutant protein from being cleaved and releasing the N-terminal fragment
What is important for cytological screening for cervical cancer? What is a way in which this is achieved?
-Important to have a low threshold of detection -Partly achieved by including an ASCUS classification
What are the effect on incubation time of AA substitutions within PrP^c?
-Increase incubation time -some prevent disease
In what animal was scrapie infectivity purified from?
-Inoculated hampsters (led to higher infectivity)
What does integration do to the HPV DNA?
-Interrupts the E2 ORF -E2 becomes inactive
How were the shortest incubation times for inoculation of prion proteins achieved?* What is the significance?*
-Intracerebral inoculation with a protein sequence identical to that of the host animal (the proteins vary across species) -creates a species barrier
Why is the prevalence of HPV hard to determine?
-It is so common -Often tested by serology
What classifications of cervical cells can be determined by cytology?
-LSIL -HSIL
What are the positives of a pap smear?
-Low cost, complication and morbidity -minimally invasive -easy to do
Which type of neurons are primarily affected by HD?
-Medium sized spiny projection neurons (indirect pathway)
What kind of tissue is the transformation zone? What is the significance?
-Metaplastic -particularly susceptible to the carcinogenic potential of persistent HPV infections -where cervical cancer usually arises from
Describe the improved model of prion diseases
-Mice expressing different levels of wt hampster PrP transgene
How was PrP^Sc found to be different than PrP^c?
-More alpha helical structure in PrP^c -More beta sheet structure in PrP^Sc
What model systems are used for HD now? Which is the most common?
-Mouse= some transgenic (with human gene), some knock out [most common] -Pig, sheep, monkey
What are the possible etiologies of familial fatal insomnia?
-Mutation (D178N- aspartate to asparagine) -sporadic (non-mutated)
Explain how amyloid fibrils are formed in polyQ diseases
-Native monomer has many alpha helical domains -folding patterns change to a predominance of beta sheet -beta sheet monomers form oligomers -beta sheet oligomers can polymerize to form amyloid fibrils
Are all cases of HD inherited?
-No -Approx 1-3% cases arise from a de novo mutation
Can cervical intraepithelial dysplasia be tested for by serology? Why?
-No -The virus stays in the epithelium, so does not mount a systemic immune response
What are the 4 diagnostic classifications of cervical cells?
-Normal -LSIL (viral infection but not pre-cancer) -HSIL (pre-cancer/progression) -Carcinoma
Describe how a normal patient vs a HD patient differ in gel analysis of the trinucleotide repeat in the Huntingtin gene
-Normal patient displays 2 bands (one from each chromosome) in the normal range -HD patient has one band in the normal range, but one band above the normal range
What is the normal distribution of NMDA receptors? How is this changed in HD?
-Normally most are located at the synapse, with some extrasynaptic receptors -In HD, there is an increase in the number of extrasynaptic receptors
Are repeat expansions seen in maternal transmission of HD?
-Not really -Equal numbers of expansions and contractions are seen, and these are typically small (1 to 3 repeats)
Describe the most common diagnostic test for HD
-PCR across the trinucleotide repeat region -calculate how many repeats based on the size of the fragment -sensitivity is very high
What is QBP1? What does it do?
-PolyQ Binding Peptide 1 -prevents the toxic beta-sheet conformation transition of the expanded polyQ monomer -inhibits neurodegeneration
Explain the prion hypothesis
-PrP^Sc and PrP^c interact along with a third protein (protein X) -PrP^Sc replicates, using the normal protein as a substrate -more PrP^c is converted to PrP^Sc -PrP^Sc works like a crystal, laying down a plaque
When is presymptomatic testing for HD performed?
-Referral from a genetic clinic -Child of an affected parent
List some TSEs/prion diseases
-Scrapie -Kuru -CJD -Transmissible mink encephalopathy -Chronic wasting disease (free ranging deer and infectious to cats) -Bovine spongiform encephalopathy (vCJD in humans) -Gertsmann-Straussler-Scheinker disease -Fatal familial insomnia
List the factors that increase the risk of HPV?
-Sex -Age -Age of first sexual intercourse -Co-infections -Male circumcision -Condom use -Life time number of partners -Other STIs (e.g. HIV)
What are the symptoms of Kuru?
-Shaking (cerebellar ataxia) -Muscle wasting -Progressive dysarthria, dysphagia -Later occuring dementia
What do animal models for HD show about ASO treatment?
-Small, but stastically significant improvement in the volume of some brain regions (striatum, cortex) -improvement in body weight -slight improvement on rotorod (mice)
How does a HD brain compare to normal visually?
-Striatal atrophy (caudate nucleus and putamen shrunken) -see an empty space near the middle of the brain
What area of the brain is primarily affected by HD? Where is it?
-Striatum (composed of the putamen and caudate nucleus) -deep within the grey matter of the brain
Describe the current treatment for HD
-Symptom management (treat chorea, behaviour) -Surgical intervention (cell replacement, DBS) -Functional approaches (replacing things that are lost= energy, cell death) -Aggregation modulator (antibodies, chaperones) -Removal or prevention of aggregate (increase autolysis, genetic engineering)
What were the results of female vaccination against HPV?
-The percentage of women diagnosed as having genital warts went down -The percentage of men diagnosed with genital warts also significantly decreased
What is HPV gene expression related to?
-The state of differentiation of the infected epithelium -suprabasal epithelial cells= early gene expression -terminally differentiated karatinocytes= late gene expression
What is the goal for funtional approaches for treatment of HD? Why is this difficult?
-To replace all the cellular functions that are lost in HD -Difficult because there are many things to correct
List the toxic effects of the mutant huntingtin protein in HD
-Transcriptional dyregulation -Decreased levels of BDNF production -Disruption of axonal transport -Synaptic dysfunction and resulting excitotoxicity -Mitochondrial dysfunction and generation of ROS -Impaired protein recycling by the ubiquitin-proteosomal system (UPS) -Apoptotic neuronal cell death -Altered Ca2+ influx/homeostasis -Altered RNA metabolism -Protein accumulation (improper proteosome degradation)
What are some of the functions of the normal huntingtin protein?
-Transcriptional regulation (interacts with an array of TFs) -regulates BDNF (brain derived neurotrophic growth factor) production -vesicle trafficking/ axonal transport -Downregulation of glutamate receptors -Anti-apoptotic
What can induce autophagy and is in animal trials for treatment of HD?
-Trehalose (natural sugar) -induces autophagy and degradation of aggregates -has been shown to inhibit aggregation to some extent
What patterns of PrP^Sc were defined for vCJD and BSE? What is the significance?
-Type 4 -Novel pattern compared to sCJD and iCJD
What is the result of the majority of HPV infections?
-Viral clearance -development of type-specific immune response
What caused a mini-scrapie epidemic in 1946? What was the significance?
-When it was accidentally transmitted through formalinized vaccine prepared from sheep CNS -The disease agent is therefore resistant to formalyn
What are some potential future therapies for HD?
-Zinc finger proteins to inhibit transcription -ASO, siRNA to eliminate RNA -Anti-aggregation agents
How are the epithelial cells involved in HPV infection?
-act as a reservoir for virus -when opened, release the virus
Describe spongiform degeneration/vacuolization (seen in sCJD)
-affects cortical grey and deep grey matter -often accompanied by reactive gliosis and plaque formation -Vacuoles represent swellings of axonal and dendritic neuronal processes, associated with the loss of synaptic organelles and accumulation of abnormal membranes
Describe intrabody generation for treatment of HD
-an intracellular antibody against the mutant HD protein (the polyQ tract) -mice show fewer aggregates in their brains and do better on motor tests
How was prion disease spread in the food chain?
-animal feed was made from ground up beef and sheep products from British slaughterhouses -feed was given to ruminants, poultry, etc -danger of infecting new species and perpetuating the original strain
Describe the genome of HPV
-approximately 7900 bp -8 ORFs -encodes 6 early proteins and 2 late structural proteins
Describe the majority of HPV infections?
-asymptomatic -cleared by the immune system
What are the clinical features of GSS?
-ataxia of gait -dysarthria -pyramidal and extrapyramidal symptoms -often late development of dementia
How does a brain affected by sCJD appear macroscopically?
-atrophied -ventricles become enlarged due to loss of brain tissue
What is the inheritance pattern of Familial/genetic CJD?
-autosomal dominant -high penetrance
Why is it advantageous for HPV to express viral proteins in the keratinocytes?
-avascular area -limited access for the immune system
What cells do HPV infect? What is significant about these cells?
-basal keratinocytes -they are metabolically active (important for viral infections)
Why is there a push to include boys in the HPV vaccination program?
-because they are a reservoir -potential for infecting women later in life with waning immunity
How does tetrabenazine work?
-binds to VMATs, preventing the transporters from allowing dopamine particles into vesicles -also competes for the postsynaptic dopamine receptors
What does the treatment of cervical lesions depend on?
-biopsy diagnosis -age of patient
How can a carcinoma be predicted from a pap smear?
-cannot be seen directly from a smear -prominent nucleoli suggests that it is at least an HSIL, suspect that it could be invasive
How else does huntingtin protein affect NMDA receptors?
-causes aberrant trafficking of an unconventional NMDAR subunit (GluN3A) -huntingtin interferes with endosomal removal of GluN3A from the postsynaptic membrane -GluN3A has reduced Ca2+ permeability
How often is HPV responsible for cancers?
-causes virtually all cervical cancers -causes approximately 4% of other cancers
How does iCJD typically present?
-cerebellar ataxia rather than cognitive problems -EEG shows diffusely slow wave pattern (rather than periodic discharges)
Describe the LSIL diagnostic classification
-cervical changes -early lesions -evidence of HPV (may be low risk) -can be detected by molecular tests
How was the problem of BSE dealt with?
-changes to the laws concerning usage and export of animal feed -testing of slaughtered animals
What are the possible outcomes of HPV infection?
-clearance -persistence (steady state) -progression to precancer
What are some tests for HPV?
-colposcopy -DNA -Serology
Describe the PRNP gene
-constitutively expressed in humans -highly conserved among species -highest level of expression in neurons
What things were discovered about scrapie by using animal models?
-could be experimentally transmitted to mice -some sheep breads are susceptible, some are resistant
Describe what occurs after pap smear results
-decided if patient needs to see a specialist -specialist uses colposcopy to look for a lesion and see if a biopsy is needed -biopsy confirms the findings of a lesion -removal/treatment
Where does HPV want to get to upon infection? How does it do this?
-deep into epithelium (germinal cells in the basal layer) -presumably via tiny tears in the mucosa
What proportion of persistent HPV infections progress to pre-cancer?
-depends on the type of HPV -as many as 40% of persistent HPV 16 infections after 3-5 years
What does traditional management of scrapie involve?
-destroy flock and abandon field -fear or reintroduction
Explain how scrapie infectivity was purified
-detergent extraction -limited digestion with proteases and nucleases -differential centrifugation -agarose gel electrophoresis (separates protein from nucleic acid) -sucrose gradient purification
What occurs in a small proportion of individuals infected with HPV?
-develop genital warts -even smaller proportion develop cancers
What are the effects of Prnp knockout mice?
-develop normally -mice inoculated with prions are resistant to infection
What is the uptake of predictive vs diagnostic testing for HD?
-diagnostic is high -predictive is low
How can prion incubation times and replication be altered?*
-dose -route of inoculation -level of PrP^c expression (high increases progression) -species of prion -prion strain
What are the clinical features of familial fatal insomnia?
-dysautonomia -ataxia -variable pyramidal and extrapyramidal signs/symptoms -relatively spared cognitive function (until late course)
Describe the management of an LSIL cytological diagnosis
-either direct colposcopy or repeat cytology in 6 months -if cytology negative, repeat in 6 months , if negative again return to normal screening -if secondary cytology greater than ASCUS, refer to colposcopy
Describe the parent of origin effect for trinucleotide expansion disease
-either parent can pass down the mutant allele -actual expansion event only happens in one germ line (maternal or paternal)
Describe the path of HPV infected basal cells
-enter the suprabasal cell layer -associated with increased expression of early (E4, E5, E6, E7) and late proteins -viral assembly occurs in the terminally differentiated epithelial cells (L1 and L2 proteins) -the virions are then released in to the surrounding tissues, spreading infection
How does the histology differ in LSIL?
-epithelium is less organized -large, dark nuclei -binucleation -exaggerated clear space around nuclei
Describe the regulation of E6 and E7 during HPV infection
-expressed at low levels during the infectious process -at some point in progression to pre-cancer, E6 and E7 expression is deregulated by either genetic or epigenetic changes -leads to overexpression in the full-thickness epithelial lesion
Which forms of prion disease can be inherited?
-fCJD -GSS -Fatal familial insomnia
What are some examples of complications in late HD?
-falls -aspiration -pneumonia
What are the pros for predictive testing for HD?
-family planning -info for children
What is done post treatment of cervical lesions?
-follow up colposcopy and pap smear (ensure that the margins are clear of abnormal cells) -perform a second attempt if abnormal cells are found in the margins -return to routine screening
How does histology differ in HSIL?
-full thickness expansion of basal cells -no evidence of invasion -Cells have high nucleus:cytoplasm ratio (makes them look darker)
Describe how the mitochondria contribute to the symptoms of HD and how this was reasoned
-function is impaired in HD -oxidative stress impairs mitochondrial function, mimics some HD physical brain changes in mice
Describe how ASO treatment is designed
-genotype patient -find heteroxygous SNPs in the HTT gene -develop ASO drug to target distinct SNP
Describe direct HPV testing
-get the same pap smear -use a sequencing machine to test for the presence of HPV -If HPV detected, a sample is sent to a pathologist to confirm a lesion
What are cervical screening programs good and not good at detecting?
-good at detecting the majority of cervical cancers (squamous cell carcinomas) -not very good at detecting cervical adenocarcinomas
Describe the HSIL diagnostic classification
-higher risk -not cancer yet -cells can get out of the epthelium
Outline some of the economic and political burdens caused by BSE
-hundreds of thousands of cattle slaughtered in Britain -loss of many jobs -threatened European unification
What are early proteins of HPV associated with?
-immune evasion -structural -enzymatic
What are some effects of HD in the nucleus?
-impaired transcription -proteosome impairment -protein inclusions and mifolding
What is proof that more than just loss of normal function of the huntingtin protein leads to HD?
-in rare individuals who inherit the HD mutation from both parents, they have similar ages of onset of symptoms to heterozygous individuals with equivalent expansion -note: homozygotes do have a more rapid clinical deterioration
What are the symptoms of scrapie?
-increased chewing -ataxia -unable to keep up with flock -itchiness -anorexia -wasting -death
Describe some of the features of HD
-increasing emotional, cognitive and psychiatric problems -depression is very common -suicide 5 to 10 times general population -muscle wasting and weight loss (despite normal caloric intake)
Describe cytological screening for cervical cancer
-individual cells (from pap smear) -Bethesda system -Normal, ASCUS, LSIL, HSIL, Carcinoma
What gives rise to vCJD?
-ingestion of meat from cows with BSE
Describe the infection process for vCJD
-injested -survives the digestive juices -enters small bowel -transported by lymphatics to the spleen -enters the CNS via the spine -travels into the brain
What are the cons for predictive testing for HD?
-insurance concerns -lack of effective treatment options
Describe the relationship between HPV integration and invasion
-integration is associated with invasive cancer -Not all women with invasive cancers have measurable integration, so integration may not be necessary to cause invasion
How are HPV genotypes divided?
-into different risk groups -stratified according to their oncolytic properties
What can occur to HPV in a precancer stage?
-invasion to true cancer -regression to normal HPV infection
Why are the sample size for fetal cell transplantation for HD small?
-invasive procedure -minimal benefit
What did Prnp knockout in mice sometimes cause?
-knock out of flanking sequences -lead to aberrant expression of prnd (another prion gene) -resulted in cerebellar degeneration
What happens when HPV E2 is disrupted by viral integration?
-lack of inhibition of E6 and E7 -results in ubiquitination of p53 and pRb -targets p53 and pRb to degradation by the proteosome -promotes uncontrolled cell division -allows for cell with DNA damage to divide -increases the risk of cancer development
Describe colposcopy
-look specifically at the suspected lesion on the cervix -decide whether or not to do a biopsy
How does HPV change in the later stages of infection?
-loses ability to produce viral capsids and early proteins -seems to focus entirely on replicating the DNA of the virus -therefore, the virus may not be infectious by the time of cervical cancer
What 2 factors contribute to the pathogenesis of HD?
-loss of normal function (neuroprotective effect of normal huntingtin) -gain of toxic function (mutated huntingtin)
How do Kuru and CJD appear on histological examination?
-lots of spongiform change in the nervous system -proliferation and hypertrophy of astrocytes within the cerebral cortex and pontine tegmentum
Which techniques were used to isolate the causative agent of scrapie?
-lysate transmission (mice, hampsters) -fractionation -sedimentation studies
How was scrapie found to be infectious?*
-made a lysate of scrapie brain and inoculated into another sheep -demonstrated sheep-to-sheep transmission
What are the early HPV proteins responsible for?
-maintaining and amplifying genomes -expressed at low levels in the epithelium
What is the significance of GABA in HD?
-major inhibitory transmitter in the brain -loss of function in HD= loss of inhibition -overall effect is a gain of abnormal function
Explain how ASO to treat HD works
-make an antisense oligo to the target (so that it doesn't bind to the normal allele transcript) -binding either recruits the RISC complex to repress translation or the oligo contains an RNase that degrades the transcript
Describe how DBS for HD treatment works
-make burr holes in the skull and implant electrodes -implant pulse generators under the skin -pacemaker to electrically reset neurons
How can genetics contribute to human prion disease?
-many insertions and point mutations/polymorphisms in PRNP associated with prion diseases -cause GSS syndrome, CJD
Explain the protein interactions with huntingtin
-many proteins physically interact with huntingtin (~380?) -when huntingtin goes wrong, all the interacting proteins are affected
How do the effects of trehalose differ in human and mouse models of HD?
-mice models show improvements in symptoms -not much proof of improvement in humans
What are the most common forms of CJD?
-most common is sCJD (85-95%) -next is fCJD (5-15%)
Where is prion protein produced?
-mostly in the brain -peripheral tissues (heart, lung, kidney, pancreas, testis) -WBCs, platelets
What clinical features/ laboratory results lead to a confirmed diagnosis of CJD?
-mutations in the PRNP gene (fCJD) -detectable PrP^Sc in brain biopsies -Detectable PrP^Sc in tonsillar biopsy (vCJD)
Describe the location of the transformation zone
-near the cervical os -moves based on the stage of the menstrual cycle and age of the patient (hormonal environment)
List the general neuropathologic features of prion diseases
-neuronal loss -vacuolization/ spongiform change -gliosis -prion amyloid plaques
What are the pathological findings of familial fatal insomnia?
-neuronal loss and astrogliosis in thalamus, inferior olives and cerebellum -MINIMAL vacuolization
How does the brain appear in Kuru?
-neuronal loss, gliosis, spongiform changes in the cerebral and cerebellar cortex -cortex shows microcysts= spongiform encephalopathy
How do classical CJD and vCJD compare in the presence of prion in lymphoid tissue?
-no detected in classical -readily detected in variant
What was found by comparing PrP^c and PrP^Sc proteins using MS and gas phase sequencing?
-no size difference -no post-translational differences
Why can ASO only target the abnormal (Huntington) allele?
-normal huntingtin protein is required -homozygous knockout is embryonic lethal
How does HPV avoid eliciting danger signals?
-not a cytolytic virus (does not cause cell death) -not associated with viremia (no systemic response) -does not activate inflammatory markers
Describe the timing of identification of BSE infected cows vs the diagnoses of vCJD
-number of infected cows peaked in 1992 -diagnoses peaked in 2000 -takes time for exposure to appear clinically
Describe the typical timeline of cervical cancer progression
-occurs in 10 year chunks -typically first infection is at age 15-25 -progression to precancer at age 25-35 -invasive cancer at 35-45
Describe the replication of HPV viral DNA in the basal keratinocytes
-occurs in an episomal fahion -low rate (50-100 copies per cell) -does not kill the basal keratinocyte
Describe genetic anticipation of HD
-occurs in some degree, especially with paternal transmission -paternal transmission increases the likelihood of juvenile onset HD
Describe juvenile HD
-onset below 20 y.o. -frequently lack chorea -instead have decreased spontaneous and voluntary movements (rigidity)
What are some other routes of prion inoculation?*
-oral -intravenous -subcutaneous -though these are slower than intracerebral
What are the late proteins of HPV associated with?
-outside structure -assembly proteins
How many types of HPV have been identified and how many are believed to exist?
-over 100 identified -believed that over 200 exist based on partial sequence fragments
What are the late HPV proteins responsible for?
-packaging the virus -expressed later/deeper in epithelium
What is the main idea about the Algorithm for the irritability treatment in HD?
-perform reassessments and adjustments throughout treatment -ends with trying something else -any treatment not likely to work for the long term
Describe the process of autophagy
-phagophore engulfs aggregtate prone proteins forming the autophagosome -autophagosome fuses with the lysosome to form the autolysosome -autolysosome degrades aggregate-prone proteins -leads to a reduction in aggregates and toxicity
What can give rise to iCJD?
-pituitary growth hormone extracts -corneal transplants -dural grafts/flaps -intracerebral electrodes -blood transfusions
What 2 characteristics predict clinical and pathological features in sCJD?
-polymorphism at 129 -digestion product length
What is the function of TGF-B?
-potent immuno-modulator -shuts off the immune response -tightly regulated
What part of the body does HD affect?
-primarily neurodenerative (brain) -does not exclusively affect the brain
Describe the kinetics of subcutaneous prion inoculation in Swiss mice
-prion titer rapidly increases in spleen (1 month) -at 3 months, the highest titer is in the brain
Describe medium sized spiny projection neurons
-project out of the striatum -release several neurotransmitters (enkephalin, GABA) -have spines (synapses) on their dendrites
List the basic characteristics of prions
-protein infectious agents -behave like viruses -non-immunogenic -lack nucleic acid genomes -exist in multiple molecular forms
What part of the Huntingtin protein is key to its toxic pathogenesis?
-proteolytic cleavage of the protein generates an N-terminal fragment containing the polyglutamine expansion
List the clinical presentations of vCJD
-psychiatric features (apathy, depression) -painful distal sensation
List the clinical features of sCJD
-rapid progressive dementia -cerebellar ataxia -myoclonus (muscle jerks) -muscle wasting
What clinical features/laboratory results lead to a possible diagnosis of CJD?
-rapidly progressing -myclonus -ataxia/other motor abnormalities -MRI with cortical rimming (sCJD) or pulvinar sign (vCJD) -family history/documented exposure -triphasic EEG complexes
Describe repeats of 36-39 in the huntingtin gene
-rare -associated with reduced penetrance (some develop HD, others do not) -may be some polygenic influence involved
Why were model systems for HD developed?
-rare disease -many clinical trials -not enough patients to take part in the clinical trials
How are the HPV vaccines made?
-recombinant technology -proteins form virus-like particles (VLPs) of the L1 protein
Describe the management of women younger than 30 after an ASCUS cytological diagnosis
-repeat cytology in 6 months -if negative, repeat again in 6 months -if second test is negative, return to routine screening (3 years) -if either of the tests return a result that is greater than an ASCUS, refer to colposcopy
Describe the typical triage after an ASCUS/ LSIL pap smear
-repeat pap in 6 months -if still abnormal, refer to colposcopy
How can HD develop in a child born of unaffected parents?
-repeats of 27 to 35 in the father can be meiotically unstable -during gametogenesis, the repeat can expand to sometimes 40 or more (if this occurs there is a 50% of inheritance)
Describe how fetal cell transplantation for treatment of HD works
-replace dead neurons with stereotaxic injections of fetal neuroblasts into the striatum -usually porcine neuroblasts
What did early models of HD rely on? What was the problem with this?
-replicating the cell death seen in HD by adding toxins to cell culture -Now know that there is much more to HD than loss of cells
What happened when hampster PrP overexpressing mice were inoculated with hampster prions?*
-resulted in shorter incubation time -abrogated the species barrier
Describe the features of normal prion protein
-rich in alpha helix -protease sensitive -detergent soluble -non-infective
Describe the features of pathogenic prion protein
-rich in beta sheets -infectious -insoluble -protease resistant (has a protease resistant core
Describe the process of a pap smear
-scrape off part of the squamous epithelium from the transformation zone -spread onto a slide, visualize individual epithelial cells (mostly squamous)
What are the 2 ways that HPV has been tested for in meta-analysis studies?
-serology -PCR
What occurs 15-20 years after clinical onset of HD?
-severe physical and mental decline -results in death due to complications
How is HPV transmitted?
-sexual contact -close personal contact (skin-skin) -contact with a mucous membrane
Describe the physical attributes of Papillomaviruses
-small -non-enveloped -circular dsDNA genome
What are some external risk factors that increase the risk of pre-cancer and cancer among women infected with carcinogenic HPV?
-smoking -multi-parity -long term ORC use
Which products from polyQ diseases cause cytotoxicity?
-soluble beta-sheet monomers -beta-sheet oligomers -possibly amyloid fibrils
Why do the majority of people infected with HPV not go on to develop cancer?
-some of the mechanisms of the virus itself -the bodies immune system
How may ASCUS appear on a pap smear slide?
-somewhere shy of an LSIL -hint of enlarged nuclei, halo -may be a single binucleate cell
What makes a good diagnostic test?
-specific -sensitive -economical -treatment options
What happens to the brain over the course of a prion disease?
-spongiform change -degeneration -brain tissue gets replaced with proteinaceous material
List the pathologies associated with prion disease
-spongiform encephalopathy -formation of prion protein fibrils -formation of amyloid plaques, wth PrP as their core constituent -Reactive gliosis -Neuronal loss -May end up in other organs as well
Describe how a infectious prion protein is created
-start with PrP^c (209 AAs) -conformational change leads to PrP^Sc (more beta sheet structure) -then broken down by proteases to the infectious polypeptide, PrP^27-30 (~142 AAs)
Describe the Ontario HPV vaccination programs
-started in 2007 -initially offered to Gr.8 girls -expanded in 2012 to include girls in Gr.9-12 -Boys not covered by vaccine program yet
What are pig, sheep and monkey model systems of HD used for?
-study behavioural characteristics -study response to gene therapy
How can protein misfolding be targeted for treatment of HD?
-target proteins before they misfold -interfere with posttranslational modifications that promote misfolding -inhibit buildup of the aggregates by stimulating clearance
What are the benefits of direct HPV testing?
-testing negative provides greater reassurance -can indicate who should go to colposcopy more efficiently -can be used post-colposcopy if no pre-cancer is found -can be used to confirm cure post treatment
Describe the anatomy of the cervix
-the cervical os is the opening between the vagina and uterus -entire surface is lined with an epithelial layer
Describe the proposed mechanism of expansion in trinucleotide repeat diseases
-the polymerase encounters the repeat region and stalls (may drop off and restart) -the opposite strand continues synthesis -the oppposite strand forms a hairpin loop of the repeat
How do the outcomes of a persistent HPV infection change over time?
-the risk of a pre-cancer diagnosis rises -probability of eventual clearance falls
What was a major discovery seen in a monkey system of HD? How?
-transgenic monkey with GFP linked form of huntingtin to see where it is expressed -showed that it is expressed everywhere
What is Kuru? How was it transmitted?
-transmissible spongiform encephalopathy -transmitted by cannibalism
What is the incubation period for HPV?
-unclear -3 months to several years
What does HPV integration lead to in the host cell?
-uncontrollable oncogene production -host cell transformation
What are some of the symptoms of Kuru?
-uncoordination -wasting away -anorexia
Other than cervical, what other cancers is HPV sometimes responsible for?
-vaginal -vulvar -penile -anal
Describe the clinical sensitivity and specificity of HD
-very close to 100% -If you have the repeat, you will have HD -if you have HD, you will have the repeat
What are some mechanisms used by HPV thought to play a role in cancer development
-viral integration -DNA methylation -chromosome instability -telomerase activation
What are the difficulties with serology for HPV?
-virus could evade the immune system -antibodies may not be present if exposed many years ago and have not been exposed again
What are significant about prion genes?
-we all have the genes (endogenously encoded) -usually produce a normal cellular prion protein
What is the transformation zone of the cervix?
-where the epithelial cells of the cervix transform from squamous to glandular located near the os -particularly susceptible to HPV infection -where early lesions will be (therefore the target of pap smear) -squamous are on the vaginal side (ectocervix), glandular are on the uteral side (endocervix)
How does the age of onset and course of vCJD compare to sCJD?
-younger population (17-42) -die at a younger age -more protracted course (13-14 months)
Describe the 2 licensed vaccines for HPV
1) Gardasil- Quadravalent (types 16, 18, 6, 11) 2) Cervarix- Bivalent (types 16, 18)
Describe the management of women older than 30 after an ASCUS cytological diagnosis
1) HPV testing -if negative, repeat cytology in 12 months -if positive, refer to colposcopy 2) If HPV testing not available, same treatment as a younger than 30 patient
Describe the 4 major steps in cervical cancer development
1) Infections- of the metaplastic epithelium at the cervical transformation zone 2) Persistance 3) Progression- of persistently infected epithelium to cervical precancer 4) Invasion- through the basement membrane beneath epithelium
Describe the 3 etiologies of prion disease
1) Infectious- exposure to prion protein starts a cascade causing normal to convert 2) Genetic- mutation in PRNP 3) Sporadic- spontaneous misfolding to create PrP^Sc
5 reasons to study prions?
1) Interesting biology and pathomechanism 2) Novel class of infectious agents 3) They cause a group of fatal diseases for which there is no treatment* 4) We are exposed to prion-containing animal products 5) Many other neurodegenerative diseases have prion-like features
Describe the 6 steps of HPV infection?
1) Micro abrasion(s) in the mucosa 2) Infects basal karatinocytes 3) Differentiates and moves to the distal mucosa 4) Viral assembly as cells move to the mucosa 5) Infectious viral shed 6) Chromosomal integration
List the 7 steps in cervical cancer prevention
1) Screening (pap smear) 2) Triage of equivocal results 3) Colposcopically guided biopsy of abnormal screening results 4) Decision whether to treat 5) Treatment 6) Post-treatment follow-up 7) Return to normal screening if possible
What are the 4 forms of CJD?
1) sCJD= sporadic 2) fCJD= familial 3) iCJD= iatrogenic 4) vCJD
Describe the steps of forming aggregates in HD
1) soluble, non-toxic protein (can be degraded by the proteosome) 2) Soluble toxic (no longer degraded by the proteosome) 3) Insoluble toxic (leads to primary pathology) 4) Forms aggregates (may lead to secondary pathology)
How long does it take to clear the majority of HPV infections?
1-2 years
How long is the course of fCJD?
1-5 years
What percentage of HPV infections persist?
10%
What is the normal number of repeats in the Huntington gene?
10-26 -polymorphic, so varies between people and alleles
What is the penetrance of HD (in people with over 40 repeats)
100%
How many injections are needed for the HPV vaccine (currently)?
2
How long is the course of GSS?
2-6 years
At what age is there a dramatic increase in cervical cancer?
20 to 45 years of age
What proportion of large cervical pre-cancers invade?
20-30% after 5-10 years
What is the average age of diagnosis of pre-cancer?
25 to 35 years
How long is prion protein?
253 AAs
What is the average age of onset of the clinical features of HD?
37 years
What is the risk of pre-cancer after 3-5 years of persistent HPV 16 infection?
40%
What is the age for familial fatal insomnia?
45 years +/- 10 years
How long does it take for initial HPV infection to progress to cancer?
5 to 35 years
Approximately how many Huntingtons patients are able to be treated by ASO?
65-70%
What is the median age of death from sCJD?
68
What length of repeat invariably causes juvenile HD?
70 or more
What is HPV 6 and 11 responsible for?
90% of genital warts
Describe the efficacy of the HPV vaccines
96% or more against the combined endpoint of CIN1,2,3
What did the differential effects of scrapie based on sheep bread lead researchers to hypothesize?
A genetic hypothesis
How long are the HPV vaccines efficacious for?
A mean of 3.7 years among females aged 15-26 years
What was found by purifying scrapie infectivity?*
A protease resistant polypeptide (Prp27-30) that was enriched in infectivity
What is the progression of HPV likely to be classified as at the infection and CIN1 stage
ASCUS/LSIL
What is common to all prion diseases
All have aberrantly folded PrP
What is part of the problem with mutant huntingtin protein
Altered interactions with the proteins that the normal protein interacts with
What is a fomite?
An inanimate object that can carry infectious agents
What lead to the discovery of the expansion in HD?
Anticipation
What does ASO stand for?
Antisense oligonucleotide OR allele specific oligonucleotide?
Where are cervical cancer rates higher?
Areas without cytology screening programs
What is the inheritance of Gerstmann-Straussler-Scheinker Syndrome?
Autosomal dominant
What is an advantage to HPV of replicating at a low level?
Avoids immune recognition
What did prion disease spread in the food chain lead to?
Ban in use of feed in the EU, and eventually other countries
Why were HGH injections once a cause of CJD?
Before recombinant protein growth hormone was obtained from the pituitary of a donor
What is ultimately responsible for the toxicity in HD?
Beta-sheet monomers and oligomers
At what stage of HPV progression does integration and upregulation of viral oncogenes occur?
CIN2
What is the most common human prion disease?
CJD -represents 85% of all human
Compare the main histopathological features of the major prion disease subtypes
CJD= spongiform degeneration GSS= PrP plaques Familial fatal insomnia= gliosis vCJD= floroid plaques (plaque with spongiform degeneration surrounding)
What is significant about HPV being non-enveloped?
Can be spread by skin-skin contact (sexual contact not required)
What was discovered to be the root cause of the Kuru epidemic?
Cannibalism
What is the downside of a pap smear?
Cannot look at the intact structure of the epithelium
What are all types of HPV capable of?
Causing the neoplastic differentiation that leads to cancer
What does HPV interference of host cellular mechanisms first lead to?
Cervical intraepithelial dysplasia= a premalignant transformation and abnormal growth of squamous cells on the surface of the cervix
What are the first signs of HD?
Change in personality (irritable, disinhibition)
Where does HPV integrate into the host chromosome?
Chromosomal fragile site (site where the chromosome is unstable)
Describe the management of a carcinoma cytological diagnosis
Colposcopy
Describe the management of atypical squamous cells (including HSIL) cytological diagnosis
Colposcopy
How can transmission of HPV be reduced?
Condoms (do not provide complete protection)
After no size or post-translational differences between PrP^c and PrP^Sc what was left that could make Sc abnormal?*
Conformational change
What composes the cervix?
Connective tissue, collagen, muscle
What does MRI of sCJD show?
Cortical rimming
What did mouse models of creatine for HD treatment show?
Creatine reduced loss of volume in white matter, gray matter, caudate and putamen
What does CJD stand for?
Creutzfeldt-Jakob disease
What are danger signals (PAMPs) crucial for in infection?
Crucial for activation/trafficking of APCs and immune cells
What is the current treatment for prion diseases?
Currently none
How do specific mutations affect fCJD?
Different mutations associated with different clinical histopathologic picture
Who originally classified Huntington's disease?
Dr. George Huntington
What are the primary HPV oncoproteins?
E6 and E7
What is the primary transforming protein in HPV infection?
E7
How does anticipation affect Huntington's disease?
Earlier age of onset and potentially more severe disease
Where was George Huntington from?
East Hampton, Long Island
What does an increase in extrasynaptic NMDA receptors favour?
Enhances the proapoptotic pathway
What may myoclonus first present as?
Exaggerated startle response
How was Kuru proven to be infectious?*
Experimental transmission through intracerebral inoculation into experimental chimpanzees (chimp-chimp transmission)
What are the possible etiologies of Gestmann-Straussler-Scheinker?
Familial or genetic
What is the etiology of fatal insomnia?
Familial, genetic or sporadic
What are the possible etiologies of CJD?
Familial, sporadic or transmitted
How does vCJD appear in PrP immunohistochemistry?
Floroid plaque= PrP plaque with halo of spongiform change
What is an alternate probable transmission mechanisms for HPV?
Fomite mediated transmission
Where was Kuru seen?
Fore tribe in Eastern New Guinea
What is a precursor to genital cancer?
Genital warts
Where did scrapie arise initially?
Germany and England
Describe the grades of HD
Grade 0= macroscopically normal brain, 30-40% loss of neurons in striatum Grade 1= Macroscopically normal, 50% loss of neurons in the striatum Grade 2= Macroscopically visible atrophy, neuronal loss evident without quantification Grade 3= Macroscopically severe atrophy, further neuronal loss Grade 4= Macroscopically very severe atrophy, >90% neuronal loss
What is a requirement to develop cervical cancer?
HPV integration into the host chromosome
What is the strongest risk factor for HPV persistence and progression to pre-cancer?
HPV type
What is the progression of HPV classified as at the CIN2 and CIN3 stage
HSIL
What are the effects of Prnp heterozygous knockout mice?
Had longer incubation periods (290 days) compared to wt (170 days)
Why is it difficult to study fomite mediated transmission of HPV?
Hard to study on a virus that is very prevalent
How do HPV proteins differ between types?
High risk types tend to have variants of E6 and E7 that bind more tightly to p53 and pRb
What is HSIL?
High-grade squamous intraepithelial lesion
Which continents have the highest and lowest prevalence of HPV?
Highest=Africa Lowest=Europe
What did Stanley Prusiner win a nobel prize for?
His discovery of prions- a new biological principle of infection*
What is the susceptibility focus in vCJD?
Homozygous Met at codon129
What must testing for trinucleotide expansion diseases take into account?
How big the expansion needs to be for the disease to occur
How is CJD mainly transmitted?
Iatrogenically
What is a problem with the PCR test for HD?
If there are more the 50 or 60 repeats the PCR reaction may fail
How else can sCJD be visualized?
Immunostain for PrP, GFAP
When is predictive testing for HD offered?
In cases where there is a known family history
Where does HPV DNA usually reside?
In the infected cell cytoplasm
Describe cerebellar ataxia
Inability to coordinate balance, gait, extremity and eye movements
How can aggregates in HD be removed/prevented
Induce autophagy with autophagy enhancers
How can prion diseases manifest?
Infectious, genetic or sporadic disorders
How did protease concentration affect infectivity of scrapie lysate?
Infectivity diminished as a function of protease concentration and duration of digestion
Why was biochemistry of scrapie agent using mouse spleens and brains impossible?
Infectivity spread from one end of a sucrose gradient to the other and from the void volume
What did the identification of the polypeptide important for scrapie infectivity provide?
Informed on the genetic location of the PRNP genes in animals and humans
How does normal huntingtin protein downregulate activity of glutamate receptors
Interaction with postsynaptic density (PSD) proteins
What does IT15 stand for?
Interesting transcript 15
What is a characteristic molecular feature of CAG trinucleotide repeat diseases?
Intra-cytoplasmic and intra-nuclear beta-sheet/amyloid aggregates of PolyQ proteins
What is the significance of an increase of beta sheet structure in PrP?
It can now deposit as protein aggregates
How does the testing of slaughtered animals for prion disease compare for Canada, US, Japan
Japan= 100% Canada= 0.1% US= 0.06%
What is serology?
Looking for antibodies against a particular pathogen
What is LSIL?
Low-grade squamous intraepithelial lesion
What sex is head and neck cancer related to HPV more common in?
Males
What is the parent of origin effect for Fragile X Syndrome?
Maternal
Describe how Coenzyme Q10 improves the ETC in mitochondria
May drive more production of energy from mitochondria that are reaching the ends of their lives
What is responsible for the genetic anticipation in paternal transmission HD?
Meiotic repeat instability in paternal transmission and a tendency toward larger expansion
What is the reservoir for HPV?
Men
Which group is anal cancer related to HPV most common in?
Men who have sex with men
Why isn't immediate action taken if ASCUS/LSIL are found from a pap smear?
Most people at ASCUS/LSIL will clear the infection and the next pap smear will return normal
How are genital HPV infections mainly transmitted?
Mucosa-mucosa contact
How is the HPV vaccine believed to protect against infection?
Neutralizing IgG that transudates from capillaries to the genital epithelial mucosa and binds to viral particle
Does CJD show a sex bias?
No
What does EEG show in vCJD?
No characteristic findings (no spontaneous discharges)
What is the problem with the ASO trial?
No one has yet enrolled
What kind of viruses survive better outside the body?
Non-enveloped
What is the normal function of HPV E2?
Normally down regulates E6 and E7
How short can the lag time be between infection and the first microscopic evidence of pre-cancer?
Often within 5 years
How many species of prion can be present in a host simultaneously?
Only one
What happens to the brain as HD progresses
Other areas of the brain are affected and undergo atrophy (e.g. cerebral cortex)
How many different types of HPV infect the epithelial lining of the anogenital tract?
Over 40
What is the gene that encodes the prion protein?
PRNP on 20p
What is prion an acronym for?
PRoteinaceous Infectious particle withOut Nucleic acid
What is the parent of origin effect for HD?
Paternal
What is the most common mutation in fCJD?
Point mutations
What does PrP^Sc preferentially bind to (and convert)
PrP^c with an identical sequence
What are prions?*
Protein infectious agents that lack nucleic acids
What does MRI show in vCJD?
Pulvinar sign= thalamic nuclei lighten up
When is exclusionary genetic testing for HD peformed?
Referral from a neurology clinic
What is the time course of sCJD?
Relatively short (4-5 months)
Describe the management of an unsatisfactory for evaluation cytological diagnosis
Repeat cytology in 3 months
Describe the management of a "no transformation zone present" cytological diagnosis
Routine screening (3 years), no immediate recall required
What experimental evidence lead to the belief that a protein agent was responsible for TSEs*
Scrapie agent was... -resistant to UV light, ionizing radiation, nucleases -sensitive to proteases
What was the key to prion biology?
Scrapie disease
How common is cervical cancer?
Second most frequent cancer in women
What does Kuru mean?
Shaking
What was an issue of proving sheep-to-sheep transmission of scrapie?*
Sheep are an inconvenient animal model
What animals does scrapie affect?
Sheeps and goats
What was prion disease initially thought to be caused by?
Slow virus infection
When is prenatal testing for HD performed?
Sometimes in an individual carrying a pregnancy that knows they have the mutation
What is the characteristic pathological finding for sCJD?
Spongiform degeneration/vacuolization
What is the most common etiology of prion disease in humans?
Sporadic
Describe the typical triage after an HSIL/Carcinoma pap smear
Straight to colposcopy
What were the results of the 2CARE trial of Coenzyme Q10 for HD?
Terminated due to futility (did not help the patients)
What did PrP knockout mice tell us?
That PrP^c is a necessary substrate for TSE transmission
What is meant by the polyglutamine repeat being "unstable"
That the size of the repeat can become larger
What helped answer the question of whether scrapie was a genetic or infectious disease?
The Kuru epidemic of New Guinea
What is the efficacy of tetrabenazine assessed by?
The chorea scale (Clinical Global Impression Scale and Functional Impact Scale)
What is the reason for muscle wasting and weight loss in HD?
The disease also affects the skeletal muscle (to a lesser extent than the brain)
What is the first line of defence against HPV infection?
The innate immune system
What is the development of invasive cervical cancer closely linked to?
The integration of HPV viral DNA
How common is HPV?
The most common viral STI
What is PrP^c?
The normal cellular prion protein
What is responsible for the strain specificity of TSE?*
The tertiary structure of the protein
What happens as nerve cells in the brain degenerate?
The tissue shrinks
Where does HPV target?
The transformation zone in the epithelium of the cervix
How does HPV gain entry?
Through microtears in the epithelium/genital tract
Where does PrP^Sc deposit?
Throughout the brain
What are prion diseases also known as?*
Transmissible Spongiform Encephalopathies (TSEs)
What is PrP^Sc?
Transmissible form of prion protein
What is the etiology of Kuru?
Transmitted
What is the etiology of vCJD?
Transmitted
What patterns of PrP^Sc were defined for sCJD and iCJD cases?
Type 1, 2 and 3
What is the cause of sCJD?
Unknown
What is the proof for the mechanism of HPV vaccination?
Up to 24 months after dose 1, levels of HPV 16 and 18 antibodies in cervicovaginal secretions and serum are strongly correlated
What is the characteristic pathologic lesion of GSS?
Very large PrP amyloid plaques
Why is iCJD a problem?
Very resistant to common denaturing and sterilizing agents
What do low risk HPV types typically cause?
Warts (not pre-cancer)
When does a cervical carcinoma become invasive?
When cells break through the basement membrane underlying the stroma
When does the prion protein cause neurological diseases?
When it misfolds, resulting in protein deposition
What is genetic anticipation?
Where the clinical features of a hereditary disease develop at an earlier age and/or with increased severity as it is transmitted from one generation to the next
Who did Kuru most often infect?
Women and children
When does GSS often occur
Younger than sCJD (<55)
What is invariably associated with the pathology of prion diseases?
accumulation of PrP^Sc (PrP amyloid plaques)
Where do PrP mutations often occur to lead to TSEs?
alpha helices
How many deaths have been caused by vCJD?
approx 200
What causes the shaking in Kuru?
cerebellar ataxia
What other species can Kuru be transmitted to?
chimpanzees
Where do prion proteins arise?
encoded in donor and recipient genomes
When does fCJD often occur?
in younger people
What is the range in the age of onset of clinical features of HD?
infancy to 80's
What are PrP gene mutations linked to?
inherited prion disease (cause formation of PrP^Sc)
What is another mutation in the PrP gene that can lead to TSEs?
insertion of a repeat involved in binding copper
What often precedes fatal familial insomnia?
intractable insomnia
Describe the typical triage after a normal pap smear
repeat every 3 years
What forms of CJD are considered classic CJD?
sCJD and fCJD
How does PrP immunohistochemistry compare for sCJD vs. vCJD?
vCJD has a more prevalent accumulation of prion proteins
Describe transition from asymptomatic to HD in terms of repeat number
very abrupt
What is a risk in a persistent HPV infection?
virus chromosomally integrating
How long is the course of familial fatal insomnia?
~1 year
How long is the course of vCJD?
~1.5 years
