Cell Biology of Prions

and Prionoids
GROUP 5 BS BIOLOGY IV B
Protein Misfolding Disorders (PMDs)
• Caused by alterations in the secondary structure of proteins
• Critical thresholds Ordered aggregates PMDs
Protein Misfolding Disorders (PMDs)
• Includes each of the following diseases of the CNS:
- Alzheimer’s disease (AD)
- Huntington’s disease (HD)
- Parkinson’s disease (PD)
- Amyotrophic lateral sclerosis (ALS)
- Frontotemporal dementia (FTD)
- Prion diseases
Protein Misfolding Disorders (PMDs)
• Common features of PMDs
- loss of neurons
- abnormalities of synaptic function
- deposition of extracellular or intracellular protein aggregates
Figure 1. Model of disease progression in Protein Misfolding
Disorders (PMDs)
Protein Misfolding Disorders (PMDs)
• Prion diseases or Transmissible Spongiform Encephalopathies (TSEs)
- aggregation of cellular prion protein into beta-sheet rich aggregates
- best characterized PMDs
- caused by an agent called prion
Protein Misfolding Disorders (PMDs)
• Prion
- a propagon associated with TSEs
- various forms:
* fibrillary aggregates
* plaques
* protease-sensitive oligomers
Protein Misfolding Disorders (PMDs)
• Prions can be mistaken with protease resistant PrP because as these
assume protease sensitive oligomers, these resemble each other in
terms of higher molar ratio and biological activity and protease
sensitivity.
Protein Misfolding Disorders (PMDs)
Prions Prionoids
- Beta sheet rich propagons - PMD proteins capable of cell to
resulting in TSEs which are cell propagation within
transmissible individuals
Prion Proteins
• Prion diseases can be acquired, genetic or sporadic.
• Iatrogenic prion transmission continues to occur because it can resist
the methods of sterilization
• cellular prion protein (PrPc) can fold into various self propagating
conformations which has its own histopathological and biochemical
signature.
Cellular Prion Protein
Conformations
Prion Proteins
• termed prion strains because it is closely reminiscent of viral strains
• other conformers of PMD proteins have also been said to give rise to
strains.
• Infectious conformers of PrP are detergent insoluble and protease
resistant – not an obligate feature of prion infectivity
Prion Proteins
• PrP oligomers grow by incorporation monomers to generate
protofibrils and large amyloid deposits
• prion replication and toxicity are two distinct phenomena- some are
toxic but not self-replicating and some can accumulate into fibrils but
not elicit toxicity
Amyloid deposits Protofilaments
A ᵦ and Tau
• AD is characterized by the deposition of extracellular Aᵦ-containing
amyloid plaques and intraneuronal aggregates of hyperphosphorylated
tau protein in form of neurofibrilliary tangles and neuropil threads.
Healthy vs AD
microtubules
Alpha Synuclein
• PD is characterized by accumulation of aggregates called Lewy Bodies
in the cytoplasm of dopaminergic neurons in substantia nigra.
• produces progressive toxicity and neurodegeneration which leads to
movement disorders.
• intrinsically unstructured monomer
• Mutations on ASYN are linked to familial PD and overexpression of
wild type alpha syn is sufficient to cause PD
• levels in cytoplasm increase with age
Huntingtin
• HD is characterized by the expansion of CAG trinucleotide repeat
within the HTT gene that encodes huntingtin.
• accumulation of aggregates bearing polyQ repeats.
• occurs above a threshold of 35-40 repeats
Huntingtin
• alterations in motor function, severe cognitive impairment and
widespread cortical atrophy
• mechanisms unclear
• mice overexpressing mutant huntingtin revealed oligomers of 20-
40nm in diameter
• soluble huntingtins are the toxic species rather than the large
aggregates.
Oligomer Generation
• Oligomeric species are the key pathogenic drivers in various PMDs
• Fibrils break spontaneously when they reach the critical length
producing an equilibrium between growth and fragmentation
• studies in yeast cells identified Hsp104 diaggregase, a sophisticated
machinery that can dissolve cytosolic aggregates including the yeast
prion psi.
• overexpression of Hsp104 can cure yeast from prion psi but absence
of Hsp104 display the ‘psi-no-more’ phenotype which make them
resistant to infection
Cell- to- Cell
Spread
Exosomes: Are They or Are They
Not?
• Tiny nanoparticles
• Provides another mechanism for cell communication
• Float to destined parts of the body