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Unfolding prion diseases and their inheritance

When misfolded proteins lead to disease

Prion proteins are found abundantly in the brain; their function is unclear, but they are involved in a multitude of physiological mechanisms, including myelin homeostasis and the circadian rhythm. Correctly folded prion proteins in the cellular form are termed PrPC, while their infectious isoform is called PrPSc. As shown in Figure 1, the misfolded PrPSc is largely made up of β-pleated sheets instead of α-helices; PrPSc is prone to forming aggregates that cause transmissible spongiform encephalopathies (TSEs).


Prion diseases can be categorised by their aetiology: acquired, sporadic, and hereditary. Acquired prion diseases are caused by the inadvertent introduction of PrPSc prions into an individual.  Sporadic prion diseases are the most common type, where PrPC misfolds into PrPSc for an unknown reason and propagates this misfolding within other prion proteins. Hereditary prion diseases are caused by genetic mutation of the human prion protein gene (PRNP), which causes misfolding into the infectious isoform. Consequently, these mutations can be passed to offspring, resulting in the same misfolding and disease. Interestingly, different types of PRNP mutations cause different types of prion diseases. 


Creutzfeldt-Jakob disease (CJD) is a type of TSE found in humans which causes mental deterioration and involuntary muscle movement; symptoms tend to worsen as the disease progresses, making it a degenerative disorder. Familial CJD (fCJD) is a rare type of hereditary prion disease and can sometimes result in a faster rate of disease progression compared to sporadic cases.  Due to a dominant inheritance pattern, relatives of fCJD patients are often also affected by the disease.  The most common mutation observed in familial CJD is an E200K mutation denoting the substitution of glutamic acid with lysine in the prion protein. Other common mutations resulting in fCJD include mutations at positions 178 and 210 on the prion protein. However, there are, less frequently, a multitude of other mutations correlated with familial CJD development. Familial CJD can be caused by STOP codon mutations, which result in a truncated protein, some of which show similar pathology to Alzheimer’s disease, such as Q16OX and Q227X. 


fCJD can also be caused by insertional mutations, possibly caused by unbalanced crossover and recombination. The prion protein consists of a nona-peptide (made up of nine amino acids) followed by four repeats of an octa-peptide (made up of eight amino acids). During insertion mutations, additional repeats of the octa-peptide are present in the prion protein. Interestingly, different numbers of inserts result in different pathological characteristics; patients with 1, 2 or 4 extra repeats show similarity to sporadic CJD, while those with 5-9 extra repeats show similarity to Gerstmann-Sträussler-Scheinker syndrome. 


Hereditary prion diseases are important to study in order to develop an understanding of not only prion misfolding diseases but also diseases associated with misfolding of other proteins, such as Alzheimer’s and Parkinson’s. Understanding the mechanisms of hereditary prion diseases will aid the development of treatments for such conditions. In particular, observing and investigating particular genetic mutations observed to play a part in prion misfolding is crucial alongside using genetic information to infer the risk of disease an individual may have. 


Written by Isobel Cunningham

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