By Mary L. Vo, MD, PharmD
Assistant Professor of Neurology, Weill Cornell Medical College
Dr. Vo reports no financial relationships relevant to this field of study.
SYNOPSIS: Sporadic Creutzfeldt-Jacob disease (sCJD), the most common form of human prion disease, is characterized as a rapidly fatal neurodegenerative process caused by propagation of a transmissible misfolded prion protein gene (PRNP). However, selective PRNP mutations only account for a small subset of sCJD cases, leading to interest in discovering additional genetic risk factors. Through a two-stage study design using genome-wide association studies, the authors have identified two novel risk loci, STX6 and GAL3ST1, which encode for proteins involved in cellular trafficking of prions and sphingolipid metabolism, respectively. These findings provide insights into sCJD pathogenesis and are an avenue for further research.1
SOURCE: Jones E, Hummerich H, Vire E, et al. Identification of novel risk loci and causal insights for sporadic Creutzfeldt-Jakob disease: A genome-wide association study. Lancet Neurol 2020;19:840-848.
Genome-wide association studies (GWAS) have been instrumental in elucidating the genetic underpinning of complex neurologic diseases by identification of pathologic single nucleotide polymorphisms (SNPs) in a group of affected individuals relative to a healthy control population. However, prior GWAS in sporadic Creutzfeldt-Jacob disease (sCJD) were not adequately powered to identify prion protein gene (PRNP) risk factors.
The current study by Jones et al at the London Institute of Prion Diseases analyzed samples from 5,208 cases of probable or definite sCJD obtained between 1990 and 2014. Genome-wide genotype data for 4,110 sCJD samples were compared to 13,569 controls. The subjects were of mostly European descent, and controls were matched to ancestry. The findings were subject to imputation using the Michigan server and downstream association tests. The threshold for genome-wide significance was P < 5 × 10-8. Two loci achieved genome-wide significance, mapping to 1q25.3 (STX6) and 22.q12.2 (GAL3ST1). In the replication stage, association testing of genotype data from 1,098 sCJD patients and 498,016 controls identified PRNP, STX6, and GAL3ST1 loci as being significant. Exome sequencing of 501 sCJD samples did not identify additional variants in GAL3ST1 or STX6.
Additional analysis did not identify a single causal variant in STX6 but did show a strong correlation between sCJD risk and increased STX6 messenger RNA (mRNA) expression in the caudate and putamen, areas most commonly affected on brain magnetic resonance imaging.
Immunohistology for syntaxin-6, encoded by STX6, was performed on 19 sCJD samples and 15 controls. Increased syntaxin-6 expression was noted in cerebellar Purkinje cells and large axons of dentate nucleus. STX6 encodes for syntaxin-6 found in the trans-Golgi network and endosomes and its function involves vesicular fusion and endosomal degradation. The endocytic-recycling compartment or multivesicular bodies are thought to be the site of prion generation. Prior studies have suggested dysregulation of cellular trafficking may play a role in sCJD pathogenesis.
GAL3ST1 encodes galactose-3-O-sulfotransferase 1, which localizes to the Golgi network in oligodendrocytes and is integral to metabolism of sphingolipids to form sulfatides. Sphingolipid metabolism and myelin maintenance have been implicated in prion protein function and prion disease.2
The authors identified significant genetic associations in sCJD that implicate intracellular trafficking and sphingolipid metabolism as important mechanisms of disease. Interestingly, risk polymorphisms in STX6 are also shared in progressive supranuclear palsy where misfolded tau protein underlies the pathology. Thus far, there is no evidence that variants in either of these risk loci alters disease progression of phenotype. However, risk variants may act at different stages of prion disease, including propensity of spontaneous prion generation, rate of prion clearance, and prion propagation.
The current study is the first to identify two non-PRNP risk loci for sCJD using GWAS. The roles of STX6 and GAL3ST1 provide insight on the role of cellular trafficking and sphingolipid metabolism in sCJD pathogenesis. Although more research needs to be done to explore the precise role of these risk variants, these findings bear potential for disease-modifying therapy.
- Jones E, Mead S. Genetic risk factors for Creutzfeldt-Jakob disease. Neurobiol Dis 2020;142:104973.
- Vallabh SM, Minikel EV. Implications of new genetic risk factors in prion disease. Nat Rev Neurol 2020; Nov 10. doi: 10.1038/s41582-020-00433-0. [Online ahead of print].