Independent protein aggregates that cause epigenetic effects are called ‘prions’. Prions are an unusual form of epigenetics. Their stable inheritance and complex phenotypes come about through protein folding rather than nucleic acid-associated changes. They are linked to chromosomal remodelling factors. Swil, a subunit of SWI/SNF chromatin remodelling complex and this protein can become a prion. Swil is cytoplasmically transmitted. This suggests that inheritance through proteins can influence chromatin remodelling and thus affect gene regulation throughout the genome.
Prions perpetuate by protein folding. A unique feature of prion-forming proteins is their ability to exist in different stable conformational states. Apart from a ‘native’ non-prion conformation, they occasionally fold into a prion conformation. This then replicates itself by templating the conformational conversion of other molecules of the same protein. These changes in conformation greatly alter the functions of the proteins involved, resulting in phenotypes specific to each determinant protein.
De novo prion formation appears to proceed through a high-energy oligomeric nucleus that is stabilized by interacting with, and converting, other prion proteins to the same conformation. The elongating prion polymer is then cut into smaller and actively growing pieces by the action of protein remodelling factors such as the disaggregase Hsp104. The resulting fragments are disseminated to daughter cells, ensuring the stable inheritance of the self-perpetuating prion template through each cell division. Prions are stable even during mating and meiosis, allowing their transmission through the germ line. Prion states are, however, reversible. Random fluctuations in prion dissemination to daughter cells, as well as changes in the activities of remodelling proteins and other factors, can generate daughter cells with the original non-prion state.
Many prion phenotypes result from qualitative changes in protein function. As the structure of the protein plays a role in determining its function, the refolding of a polypeptide into its prion form can alter the non-prion function and can even create gains of function.
Prion Diseases
The prion diseases are a large group of related neurodegenerative conditions, which affect both animals and humans. Prion diseases impair brain function, causing memory changes, personality changes, a decline in intellectual function (dementia) and problems with movement that worsen over time. The signs and symptoms of these conditions typically begin in adulthood and these disorders lead to death within a few months to several years. Familial prion diseases of humans include classic Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker syndrome (GSS) and fatal insomnia (FI) (Figure 10.4).
Figure 10.4 Prion diseases of the brain
One type of prion disease in humans, variant Creutzfeldt-Jakob disease (vCJD), is acquired by eating beef products obtained from cattle with prion disease. In cows, this form of the disease is known as bovine spongiform encephalopathy (BSE) or, more commonly, ‘mad cow’ disease. Another example of an acquired human prion disease is kuru, which was identified in the South Fore tribe in Papua New Guinea. The disorder was transmitted when tribe members ate the tissue of affected people during cannibalistic funeral rituals. Familial forms of prion disease are caused by inherited mutations in the PRNP gene. This gene encodes a protein called prion protein (PrP). Normally, this protein is likely to be involved in transporting copper into cells. It may also play a role in brain cells protection and communication. In familial cases of prion disease, mutations in the PRNP gene cause cells to produce an abnormal form of the prion protein known as PrPSc.