Prion Diseases

• Stanley B. Prusiner coined the term proin from Proteinaceous infective particle and changed to prion to sound it rhythmic.

• Prion diseases were caused by misfolded proteins.

• Elucidated the gene and mechanism by which wild type protein bring about the clinical disease.

• Degenerative diseases of the central nervous system caused by a pathogenic isoform of a normal cell protein

Prion Diseases• Prion diseases are often called spongiform

encephalopathies because of the post mortem appearance of the brain with large vacuoles in the cortex and cerebellum

• The cellular prion protein PrPc is a naturally occurring, single gene-derived gp that exists in cytoplasmic and membrane associated forms, found in neurons but also in other cells of mammals and birds.

• Prion diseases or transmissible spongiform encephalopathies (TSEs) are a family of rare progressive neurodegenerative disorders that affect both humans and animals.

Prion diseases are usually rapidly progressive and always fatal.

Characteristics• Degenerative nervous system diseases with very long

incubation periods (months to years; decades)

• No inflammatory response

• Chronic progressive pathology (slow infection)

• No remissions or recoveries: always fatal

• “Degenerative” histopathology: amyloid plagues, gliosis (Gliosis is a proliferation of astrocytes in damaged areas of the CNS. This proliferation usually leads to

the formation of a glial scar.)

• No visible virion-like structures by electron microscopy

Characteristics• No interferon production; No interferon sensitivity

• No infectious nucleic acid demonstrable

• No antigenicity

• No alteration in pathogenesis (incubation period, duration, course) by immunosuppression

• No cytopathic effect in infected cells in vitro

• Varying individual susceptibility to high infecting dose in some host species; Unpredictable ability to cross species lines

Prion Diseases• Prion

– Proteins in the nervous system that can misfold, and cause other prions to misfold

• Scrapie: – A prion disease that affects sheep

• Bovine spongiform encephalopathy: – BSE or mad cow disease

– Affects cattle that have eaten feed made with infected sheep

• Variant Creutzfeldt-Jacob disease (vCJD): – Affects humans who have eaten infected beef

Prion diseases of humans and animals

• Scrapie in sheep and goats

• Transmissible mink encephalopathy

• Chronic wasting disease in deer & elk

• Bovine spongiform encephalopathy

• Feline spongiform encephalopathy

• Kuru • Creutzfeldt-Jakob

disease• Gerstmann-

Straussler-Scheinker disease

• Fatal familial insomnia

• Variant Creutzfeldt-Jakob disease

Prion Diseases: Transmissible Spongiform Encephalopathies

• Fatal neurodegenerative diseases in man and mammals

• Transmissible under natural and experimental conditions

• Lengthy incubation period with no conventional host response

• Characteristic neuropathology with spongiform change in grey matter

• Associated with conversion of PrPC to PrPSc

Prion disease• “Prions are transmissible particles that are devoid of

nucleic acid and seem to be composed entirely of a modified protein (PrPSc).”

• “The normal, cellular PrP (PrPC) is converted into PrPSc through a post-translational process during which it acquires a high beta-sheet content.”

• PrP-C is found attached on the surface of neurons with a glycoprotein molecule. It is encoded by a group of genes located on the short arm of chromosome 20, and its function is unknown.

Prion disease Normal prions contain about 200-250 amino Normal prions contain about 200-250 amino

acids twisted into three telephone chord-like acids twisted into three telephone chord-like coils known as helices, with tails of more amino coils known as helices, with tails of more amino acids.acids.

The mutated, and infectious, form is built from The mutated, and infectious, form is built from the same amino acids but take a different shape.the same amino acids but take a different shape.

100 times smaller than the smallest known virus.100 times smaller than the smallest known virus.

Differences between cellular Differences between cellular and scrapie proteinsand scrapie proteins

PrPPrPCC PrPPrPSCSC

SolubilitySoluble Non soluble

Structure Alpha-helical Beta-sheeted

Multimerisation state Monomeric Multimeric

InfectivityNon infectious Infectious

Susceptibility to Proteinase KSusceptible Resistant

Prions: Isoform of Normal Host Protein

• Normal Protein

– Protease sensitive

– Soluble

– Found in brain tissue

– High alpha-helix content

• Disease Causing Prion

– Protease resistant

– Insoluble

– Forms amyloid fibrils

– High beta-pleated sheet conformation

These diseases involve fibril deposits: What is a fibril?

• Normal PrP or A protein may misfold into a beta sheet structure

• The beta sheets form extended aggregate fiber structures by “recruiting” properly folded proteins

• These fibrils are protease resistant and insoluble

• This is the most prevalent characteristic of amyloid and prion diseases.

Pathogenic mechanism

• If we accept the centrality of of the conversion of PrPC to PrPSc in the pathogenic process, then there are in principle three possible alternatives:

– The loss of an essential function of PrPC

– The acquisition of a toxic function by PrPSc

– Production of toxic intermediate or by-product

PathogenesisPathogenesis

Infectious particle in prion diseases

• Nonfibrillar particles between 300-600 kDa (mass equivalent to ~14-28 PrP molecules)

How do Prions “Replicate”?• When the normal prion protein changes shape it

becomes pathogenic

• Mutations can occur that make the pathogenic shape more likely

• Prions don’t replicate but they do increase in number

• When an abnormal prion combines with a normal one, the normal one changes it shape and becomes abnormal……hence the numbers of abnormal prions increases, but it is at the expense of the normal ones. No new protein is created……

Phospholipase A2 Inhibitors prevent prion replication.

Platelet-activating Factor Antagonists also inhibits prion replication.

Drugs which share a N-benzylidene-benzohydrazide core

structure.

Trimethylamine N-oxide (TMAO), can prevent formation of PrPSc.

Factors that prevent Prion Factors that prevent Prion ReplicationReplication

Gross and Microscopic Changes Gross and Microscopic Changes

Grossly there is Cortical atrophy and Grossly there is Cortical atrophy and ventricular ventricular

dilatation may also be present.dilatation may also be present.

Gross changes

ScrapieScrapie BSEBSE

CJDCJDKuruKuru

Microscopic changes

Clinical picture of Creutzfeldt-Jakob diseaseJCD

• CJD occurs in 1 person out of a million.

• In Libyan-born Israelis and in some populations in restricted areas of Slovakia the disease is 60-100 times more common.

• Other than those two examples, there is no race in which it is more common.

• It’s also as common in men as in women.

• In terms of age, it can occur anywhere between 17 and 83, but it’s more common around age 62.

• CJD occurs randomly in 90% of cases, but in 10% it’s hereditary (in which case it happens at an earlier age).

Clinical picture of Creutzfeldt-Jakob diseaseJCD

• Affected patients usually present with:• rapidly progressive dementia,

– visual abnormalities,or..– cerebellar dysfunction, including muscle incoordination

and gait and speech abnormalities. – During the course of the disease, most patients develop

pyramidal and extrapyramidal dysfunction with abnormal reflexes, spasticity, tremors, and rigidity.

– some patients may also show behavioral changes with agitation, depression, or confusion.

– These symptoms often deteriorate very rapidly– CJD is invariably fatal. Death occurs within 12 m of

illness in 85-90% of cases. Mean illness duration of 7.6 months.

Molecular hallmark of the disorder is the accumulation of abnormal prion protein(PrPSc).

Physiological functions of cellular prion protein (PrPc) is not clear.

Identity of intracellular compartment where PrPc to PrPSc occurs is not established.

Prion peptide of 106-126 residues is found to be neurotoxic.

Studies on prion protein will open the avenues for treatment of other neurodegenerative disorders.

ConclusionConclusion

What is Meningitis?What is Meningitis?

• Meningitis is an inflammation of the meninges, which, if severe, may become encephalitis, an inflammation of the brain.

• Infection of the fluid in the spinal cord and the fluid that surrounds the brain

• Viral or Bacterial

• Etiology is important because of the seriousness of the illness and the treatment needed

Causes of Meningitis

- Bacterial Infections

- Viral Infections

- Fungal Infections(Cryptococcus neoformans

Coccidiodes immitus)

- Inflammatory diseases

- Cancer

- Trauma to head or spine.

Viral MeningitisViral Meningitis

• Usually clears up in a week or two with no specific treatment

• Common; rarely serious infection of fluid in the spinal cord or fluid that surrounds the brain

• Also called aseptic meningitis

Causes of Viral MeningitisCauses of Viral Meningitis

• Caused by a number of different viruses

mosquito-borne viruses

occasionally seen after strep throat in young adults

common intestinal viruses account for half of U.S. cases per year

Signs and SymptomsSigns and Symptoms

• Usually occur one week after exposureFeverHeadacheStiff neckTirednessRashSore ThroatVomiting

Treatment and PreventionTreatment and Prevention

• No specific treatment for viral meningitis

• Antibiotics do not work on viruses

• Pay careful attention to personal hygiene

• Good hand-washing helps prevent spread of infection and viruses

Bacterial MeningitisBacterial Meningitis

• A serious infection of the fluid of the spinal cord and the fluid that surrounds the brain

• Results from bacterial invasion of membrane that covers the brain and spinal cord (meninges)

• Meninges become swollen and inflamed, leading to classic s/s of meningitis

Causes of Bacterial MeningitisCauses of Bacterial Meningitis

• Pneumococcal, Streptococcus pneumoniae (38%)

• Meningococcal, Neisseria meningitidis (14%)

• Haemophilus influenzae (4%)

• Staphylococcal, Staphylococcus aureus (5%)

• Tuberculous, Mycobacterium tuberculosis

How do people get Bacterial How do people get Bacterial Meningitis?Meningitis?

• Bacteria are spread through direct contact with secretions from the nose or throat of an infected person

• None of the bacteria that cause meningitis are very contagious

• Not spread by casual contact or by simply breathing the same air where the person infected has been sitting

Signs and SymptomsSigns and Symptoms

Under Age 2

• Fever• Headache• Stiff neck• Inactivity• Vomiting• Poor feeding• Seizures

May be hard to detect in infants

Over age 2• High fever• Headache• Stiff neck• Nausea and vomiting• Sensitivity to light• Confusion• Sleepiness• Petechiae that spreads

rapidly• seizures

Diagnosis & TreatmentDiagnosis & Treatment

• Diagnosed via lumbar puncture (spinal tap)

• Check for bacterial growth in the spinal fluid

• Antibiotic administration based on bacteria found

• Close contacts identified and treated also

• Early diagnosis and treatment important

Potential ComplicationsPotential Complications

• Advanced bacterial meningitis can lead to brain damage, coma, and death

• Survivors can suffer long-term hearing loss, mental retardation, paralysis, and seizures

VaccinationsVaccinations

• Hib vaccine (3 doses by 6 months of age and a booster between 12-18 months of age)

• Meningococcal vaccine not routinely given to civilians in U.S. because most outbreaks occur in Africa

• Pneumococcal vaccine ineffective in persons under age 2Recommended for all

persons over age 65 with certain medical problems