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 GerstmannStrausslerScheinker disease Fatal familial insomnia Variant CreutzfeldtJakob 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 acids twisted into three telephone chord-like coils known as helices, with tails of more amino acids.

The mutated, and infectious, form is built from the same amino acids but take a different shape.
100 times smaller than the smallest known virus.

Differences between cellular and scrapie proteins

PrPC PrPSC

Solubility
Soluble Non soluble

Structure
Alpha-helical Beta-sheeted

Multimerisation state
Monomeric Multimeric

Infectivity
Non infectious Infectious

Susceptibility to Proteinase K
Susceptible Resistant

Prions: Isoform of Normal Host Protein

Normal Protein
Protease sensitive

Disease Causing Prion

Protease resistant

Soluble
Found in brain tissue High alpha-helix content

Insoluble
Forms amyloid fibrils High beta-pleated sheet conformation

These diseases involve fibril deposits: What is a fibril?

Normal PrP or Ab 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 byproduct

Pathogenesis

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 dont replicate but they do increase in number When an abnormal prion combines with a normal one, the normal one changes it shape and becomes abnormalhence the numbers of abnormal prions increases, but it is at the expense of the normal ones. No new protein is created

Factors that prevent Prion Replication

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.

Gross and Microscopic Changes

Gross changes
Grossly there is Cortical atrophy and dilatation may also be present. ventricular

Microscopic changes

Scrapie

BSE

Kuru

CJD

Clinical picture of Creutzfeldt-Jakob disease JCD

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. Its also as common in men as in women. In terms of age, it can occur anywhere between 17 and 83, but its more common around age 62. CJD occurs randomly in 90% of cases, but in 10% its hereditary (in which case it happens at an earlier age).

Clinical picture of Creutzfeldt-Jakob disease JCD

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 reexes, 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.

Conclusion
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.

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 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 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 Symptoms

Usually occur one week after exposure
Fever Headache Stiff neck Tiredness Rash Sore Throat Vomiting

Treatment 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 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 Meningitis

Pneumococcal, Streptococcus pneumoniae (38%) Meningococcal, Neisseria meningitidis (14%) Haemophilus influenzae (4%) Staphylococcal, Staphylococcus aureus (5%) Tuberculous, Mycobacterium tuberculosis

How do people get Bacterial 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 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 & 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 Complications
Advanced bacterial meningitis can lead to brain damage, coma, and death

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

Vaccinations
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 2
Recommended for all persons over age 65 with certain medical problems