Misfolding & Disease

Prion Diseases and Transmissible Misfolding

Summary

Prion diseases are fatal neurodegenerative disorders caused by the self-propagating misfolding of the prion protein (PrP), where the pathogenic conformer templates the conversion of native protein in an infectious cascade.

Key Points

  • 1Prion diseases are caused by self-propagating misfolding of PrP from α-helical (PrP^C) to β-sheet-rich (PrP^Sc)
  • 2PrP^Sc acts as a template, converting native PrP^C in a seeded nucleation mechanism
  • 3Different prion strains are distinct self-templating conformations of the same protein
  • 4Human prion diseases include sporadic, familial, and acquired forms of CJD, FFI, and GSS
  • 5Prion-like mechanisms (seeded aggregation, cell-to-cell spread) operate in Alzheimer's, Parkinson's, and ALS

# Prion Diseases and Transmissible Misfolding

Prion diseases, or transmissible spongiform encephalopathies (TSEs), represent a unique class of neurodegenerative disorders caused by the infectious misfolding of the prion protein. The "protein-only" hypothesis—that a misfolded protein alone can be infectious—challenged fundamental concepts in biology and has profound implications for understanding other aggregation disorders.

The Prion Protein

Normal Cellular Prion Protein (PrP^C)

  • 208-residue glycoprotein (mature form)
  • GPI-anchored to outer leaflet of plasma membrane
  • Structure: Unstructured N-terminus + globular C-terminal domain (3 α-helices, 2 β-strands)
  • Expression highest in neurons, also in immune cells

    • Proposed Functions of PrP^C

  • Copper binding and homeostasis
  • Cell signaling (neuroprotection)
  • Cell adhesion and differentiation
  • Myelin maintenance
  • Function remains incompletely understood

    • Pathogenic Prion Protein (PrP^Sc)

  • Same primary sequence as PrP^C
  • Dramatic increase in β-sheet content (α→β transition)
  • Insoluble, protease-resistant
  • Forms amyloid fibrils and plaques

    • Mechanism of Prion Propagation

    Seeded Nucleation Model

  • PrP^Sc acts as a template or "seed"
  • Native PrP^C binds to PrP^Sc
  • PrP^C undergoes conformational conversion to PrP^Sc
  • Aggregates grow by monomer addition
  • Fragmentation generates new seeds (exponential amplification)

    • Structural Basis

  • Recent cryo-EM structures reveal parallel in-register β-sheet architecture
  • Prion strains differ in β-strand register and fibril architecture
  • Strain-specific structures are self-templating

    • Species Barrier

  • Transmission efficiency depends on sequence compatibility
  • Mismatches in key residues reduce templating efficiency
  • Can be overcome by adaptation (passage through intermediate host)

    • Human Prion Diseases

    Creutzfeldt-Jakob Disease (CJD)

    | Form | Cause | Characteristics |

    |------|-------|-----------------|

    | Sporadic (sCJD) | Spontaneous PrP^Sc formation | 85% of cases; ~65 years onset |

    | Familial (fCJD) | PRNP mutations | ~15% of cases; earlier onset |

    | Iatrogenic (iCJD) | Medical transmission | Contaminated surgery/hormones |

    | Variant (vCJD) | BSE exposure | Younger onset; peripheral lymphoid involvement |

    Fatal Familial Insomnia (FFI)

  • D178N PRNP mutation (with M129 polymorphism)
  • Progressive insomnia → autonomic dysfunction → dementia
  • Selective thalamic neurodegeneration

    • Gerstmann-Sträussler-Scheinker Syndrome (GSS)

  • Multiple PRNP mutations (P102L most common)
  • Cerebellar ataxia predominant
  • Slower progression than CJD

    • Kuru

  • Epidemic among Fore people of Papua New Guinea
  • Transmitted through ritualistic cannibalism
  • Historical proof of prion transmissibility

    • Prion Strains

    Definition

    Different conformations of PrP^Sc that breed true upon passage:

  • Distinct clinical presentations
  • Different incubation periods
  • Characteristic neuropathological patterns

    • Structural Polymorphism

  • Same protein sequence, different tertiary/quaternary structures
  • Cryo-EM reveals distinct fibril architectures for different strains
  • "Clouds" of related conformers within a strain

    • Strain Competition

  • Different strains can compete for substrate PrP^C
  • Dominant strain determined by kinetic parameters
  • Drug resistance can emerge through strain selection

    • Prion-Like Mechanisms in Neurodegeneration

    Trans-Cellular Propagation

    Multiple pathological proteins show prion-like spreading:

    - α-Synuclein: Parkinson's disease, synucleinopathies

    - Tau: Alzheimer's disease, tauopathies

    - Aβ: Alzheimer's disease

    - TDP-43: ALS, frontotemporal dementia

    Key Features

  • Seeded aggregation in recipient cells
  • Cell-to-cell transmission (tunneling nanotubes, exosomes)
  • Strain-like structural polymorphism
  • Stereotyped anatomical spreading patterns

    • Detection and Diagnosis

    Real-Time Quaking-Induced Conversion (RT-QuIC)

  • Ultrasensitive prion detection assay
  • Detects PrP^Sc seeding activity in CSF
  • >90% sensitivity and specificity for sCJD

    • Protein Misfolding Cyclic Amplification (PMCA)

  • In vitro prion amplification
  • Mimics prion replication with sonication cycles
  • Detection of minute quantities of PrP^Sc
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