Misfolding & Disease

Prion Diseases and Transmissible Spongiform Encephalopathies

Summary

Prion diseases are fatal neurodegenerative disorders caused by misfolded prion protein (PrP). Unlike other infectious agents, prions contain no nucleic acid—the misfolded protein itself (PrPSc) acts as the infectious agent, templating conversion of normal PrPC into the pathogenic form.

Key Points

  • 1Prions are infectious proteins—no nucleic acid required
  • 2PrPSc templates conversion of normal PrPC into misfolded form
  • 3Human forms: CJD (sporadic, familial, variant), FFI, GSS, Kuru
  • 4Prion strains encode different phenotypes through distinct conformations

Prion diseases represent a unique class of disorders where protein misfolding itself is the infectious and pathogenic agent, challenging fundamental concepts in biology.

The Prion Concept

Protein-Only Hypothesis

Stanley Prusiner's revolutionary proposal (Nobel Prize 1997):

- Infectious agent is protein alone (no DNA or RNA)

- Misfolded prion protein (PrPSc) templates conversion of normal protein

- The term "prion" = proteinaceous infectious particle

The Prion Protein (PrP)

Normal cellular prion protein (PrPC):

  • 209 amino acids (mature form)
  • GPI-anchored to cell surface
  • Highly expressed in neurons
  • Predominantly α-helical structure
  • Function: Uncertain; roles in copper binding, signaling, myelin maintenance

    • Pathogenic Conversion

    PrPSc (scrapie form) differs from PrPC:

  • Same amino acid sequence
  • Different conformation: β-sheet rich
  • Insoluble and protease-resistant
  • Forms aggregates and amyloid fibrils

    • Human Prion Diseases

    Creutzfeldt-Jakob Disease (CJD)

    #### Sporadic CJD (sCJD)

  • ~85% of human cases
  • Spontaneous PrPC misfolding
  • Age of onset: typically 60-70 years
  • Rapid progression: death within 6 months

    • #### Familial/Genetic CJD (fCJD)

  • ~10-15% of cases
  • Mutations in PRNP gene
  • Over 40 pathogenic mutations identified
  • Inherited in autosomal dominant pattern

    • #### Iatrogenic CJD (iCJD)

  • Transmitted via medical procedures
  • Contaminated growth hormone, dura mater grafts
  • Surgical instruments, corneal transplants

    • #### Variant CJD (vCJD)

  • Linked to bovine spongiform encephalopathy (BSE)
  • Younger age of onset (~28 years)
  • Longer clinical duration
  • Distinct pathology: florid plaques

    • Fatal Familial Insomnia (FFI)

  • D178N mutation with 129M polymorphism
  • Progressive insomnia, dysautonomia
  • Selective thalamic degeneration

    • Gerstmann-Sträussler-Scheinker Syndrome (GSS)

  • Various PRNP mutations
  • Cerebellar ataxia, dementia
  • Prominent amyloid plaques

    • Kuru

  • Epidemic in Papua New Guinea Fore people
  • Transmitted by ritualistic cannibalism
  • Historical importance: Demonstrated human transmissibility

    • Animal Prion Diseases

    Scrapie

  • Affects sheep and goats
  • Known for over 200 years
  • Name from "scraping" behavior

    • Bovine Spongiform Encephalopathy (BSE)

  • "Mad cow disease"
  • UK epidemic 1986-1998
  • Caused by prion-contaminated feed
  • Transmitted to humans as vCJD

    • Chronic Wasting Disease (CWD)

  • Affects deer, elk, moose
  • Highly transmissible in wild populations
  • Growing concern in North America

    • Molecular Mechanisms

    Templated Conversion

    The central mechanism of prion propagation:

  • PrPSc contacts PrPC
  • PrPSc acts as a template
  • PrPC refolds into PrPSc conformation
  • New PrPSc can template further conversions
  • Exponential amplification

    • Seeded Polymerization

    Nucleation-dependent aggregation:

    - Lag phase: Formation of initial seeds (slow)

    - Exponential phase: Rapid elongation and fragmentation

  • Fibril fragmentation creates new seeds

    • Prion Strains

    Different prion strains with distinct properties:

  • Same protein sequence, different conformations
  • Different incubation periods, pathology, host range
  • Conformation encodes "strain" information
  • Challenges: How does structure replicate?

    • Species Barrier

    Transmission efficiency varies between species:

  • Sequence homology matters
  • Structural compatibility of seed and substrate
  • Adaptation upon passage
  • Not absolute: BSE crossed to humans

    • Pathology

    Spongiform Change

    Characteristic microscopic appearance:

  • Vacuolation of gray matter
  • Gives brain "spongy" appearance
  • Neuronal loss
  • Astrogliosis

    • PrP Deposits

    Various deposition patterns:

  • Diffuse synaptic
  • Perivacuolar
  • Plaque-like
  • Florid plaques (vCJD)

    • Diagnosis and Therapeutics

    Diagnosis

    Challenging—definitive diagnosis requires autopsy:

    - CSF markers: 14-3-3 protein, RT-QuIC assay

    - MRI: Characteristic patterns

    - Genetic testing: PRNP mutations

    - RT-QuIC: Ultrasensitive PrPSc amplification

    No Cure Currently

    Prion diseases are invariably fatal:

  • No approved disease-modifying treatments
  • Experimental approaches: Anti-PrP antibodies, antisense oligonucleotides
  • Prevention and surveillance remain primary strategies
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    Amino Acid Side Chain Chemistry