Prions MICR 401 Group 8: Ben Saiyasombat 10/30/2012 Department of Biology and Microbiology

Background Prion: infectious agent primarily composed of protein – Does not contain nucleic acid  infectivity not affected by nucleases Discovery: – Griffith protein-only hypothesis: infectious agent consisting only of proteins – Stanley B. Prusiner: purified prion consisted of a specific protein Made up of prion proteins (PrP)

PrP -Normal form: PrP C -Cellular PrP -209 amino acids, 1 disulfide bond, kDa, alpha- helical -Readily digested by proteinase K -Function: Cell-cell adhesion, intracellular signaling -Infectious form: PrP Sc -‘scrapie’ PrP -Exact 3D structure unknown, but Higher proportion of beta sheets -Resistant to proteases

PrP Sc propogation PrP Sc has abnormal structure: – Amyloid fold, polymerization into tightly-packed beta sheets – Extremely stable, accumulates to cause cell infection and death – Resistant to denaturation Aggregations of amyloid fibers forms plaques – Converts normal proteins into misfolded form, adds on to growing fiber

Prion diseases Aggregates to form plaques known as amyloid, disrupts normal tissue structure within central nervous system – Causes transmissible spongiform encephalopathies – Affects brain/neural tissue, untreatable and fatal

Prion diseases Scrapie (sheeps and goats) – Animals scrape their fleeces off rocks, trees – Itching sensation – Convulsive collapse, excessive lip smacking, altered gaits Bovine spongiform encephalopathy (BSE) a.k.a. Mad Cow Disease – Spongy degeneration in brain/spinal cord – Long incubation period (30 months – 8 years) – Transmissible to humans Creutzfeldt-Jakob disease – Build up of amyloids in brain tissue – Dementia  memory loss, personality changes, hallucinations  speech impairments, ataxia, myoclonus – Fatal within months or weeks

Case Study A 70-year-old woman complained of severe headaches, appeared dull and apathetic, and a constant tremor in the right hand. One month later, she experienced memory loss and moments of confusion. The patient's condition continued to deteriorate, and at 2 months after onset of symptoms, an abnormal electroencephalograph tracing showing periodic biphasic and triphasic slow-wave complexes was obtained. By 3 months, the patient was in a coma-like state. She also had occasional spontaneous clonic twitching of the arms and legs and a startle myoclonic jerking response to a loud noise. The patient died of pneumonia 4 months after the onset of symptoms. No gross abnormalities were noted at autopsy. Astrocytic gliosis of the cerebal cortex, with fibils and intracellular vacuolation throughout the cerebal cortex, were seen on microscopic examination. There was no swelling and no inflammation.

Differential Diagnosis Viral Encephalitis – Herpes simplex encephalitis (HSE) Decrease in consciousness, confusion, changes in personality, more WBCs in CSF Can cause brain inflammation – California encephalitis virus (Bunyaviridae) Acute inflammation of brain Symptoms can range from minor (headaches) to severe (seizures)

Differential Diagnosis Gerstmann-Straussler-Scheinker syndrome – Difficulty speaking, ataxia progressive dementia, memory loss. May also exhibit myoclonus, blindness or deafness Creutzfeldt-Jakob Disease – Dementia, memory problems, poor coordination – As disease moves to medulla and brain stem, patient may have experience myoclonus. Some patients die due to pneumonia because of impaired coughing reflexes – Does not cause inflammation

Diagnosis: Creutzfeldt-Jakob Disease Key features – Slow virus disease, caused by prions – No swelling or inflammation, autopsy revealed fibrils and intracellular vacuolation throughout cerebral cortex, characteristic of amyloid formation – Symptoms: dementia, memory loss, confusion, followed by myoclonus. Death by pneumonia due to impaired coughing reflexes Transmission: contaminated human brain products (Immunoglobulins, corneal grafts, implants) Prevention: properly disinfect all equipment, limit exposure to contaminated products

Acknowledgments MICR 401 Class