Researchers have demonstrated that MSA and sCJD do not share similar genetic risk factors.
Neurodegenerative diseases are a very diverse group of disorders but they share some common mechanisms such as abnormally misfolded proteins with prion-like propagation and aggregation. Creutzfeldt-Jakob disease (CJD) is the most prevalent prion disease in humans. In the sporadic form of CJD the only known risk factor is the codon 129 polymorphism. Recent reports suggested that α-synuclein in multiple system atrophy (MSA) has similar pathogenic mechanisms as the prion protein.
Given this, the study set out to assess whether variants in PRNP and in particular the polymorphism status at codon 129 of PRNP gene represents a risk factor for MSA. They assessed the PRNP gene by whole-exome sequencing in 264 pathologically confirmed MSA cases and 462 healthy controls to determine whether the 2 diseases share similar risk factors. They then analyzed codon 129 polymorphism by Sanger sequencing and compared with previously published results in sporadic CJD.
Dr Viorica Chelban, first author on the paper published in Neurobiology of Ageing said: “We found homozygosity at codon 129 was present in 50% of pathologically confirmed MSA cases and in 58% of normal controls (odds ratio, 0.7 (95% confidence interval of 0.5–0.9)) compared with 88.2% in sporadic CJD. Our data show that the homozygous state of position 129 in the PRNP is not a risk factor for MSA. No other variants in the PRNP gene were associated with increased risk for MSA.”
A previous study of 300 cases of sCJD found that M129V polymorphism of PRNP was central in determining the susceptibility and pathologic phenotype in sCJD. More specifically, heterozygosity at codon 129 is protective against prion disease. It is generally believed that the protective effect of PRNP codon 129 heterozygosity relates to the fact that misfolded PrP propagation is most effective when the interacting proteins have identical primary structure.
Dr Chelban said: “Our data show a similar frequency of the heterozygous state M129V in MSA pathologically confirmed cases compared with the healthy controls. In contrast to what was previously shown for sCJD, it appears that the heterozygous state of M129V does not provide protective effects in MSA, although a larger study would be required to unequivocally determine this.”
