How cells combat prions and amyloids

2017

Challenge

As immune systems are equipped with multiple anti-viral and anti-bacterial systems, it has been hypothesized that cells must also possess anti-prion and anti-amyloid systems that can remove prions as they arise and before they can cause disease.

Advance

IRP researchers, led by Reed Wickner, M.D., and Daniel Masison, Ph.D., found that two proteins, Btn2p and Cur1p, are able to effectively remove most variants of the URE3 amyloid-based prion as they arise in yeast. Both proteins work by bringing prion aggregates together and limiting their propagation in the cell, and are homologous to the human HOOK protein family. In addition to this, researchers found that the Hsp104 chaperone can also cure most variants of the [PSI+] prion as they arise, and that both of these curing systems operate without artificial protein overproduction or deficiency.

Impact

The discovery of these anti-prion systems in yeast provides us with the opportunity to search for homologous or analogous systems in humans that are also responsible for removing prions and amyloids. If this research is successful, just as we immunize against viral and bacterial infections, it may also be possible to prime anti-prion systems in the human body to guard against prion and amyloid diseases, such as Alzheimer’s or Parkinson’s disease.

Publications

Hung GC, Masison DC. (2006). N-terminal domain of yeast Hsp104 chaperone is dispensable for thermotolerance and prion propagation but necessary for curing prions by Hsp104 overexpression. Genetics. 173(2):611-20.

Kryndushkin DS, Shewmaker F, Wickner RB. (2008). Curing of the [URE3] prion by Btn2p, a Batten disease-related protein. EMBO J. 27(20):2725-35.

Wickner RB, Beszonov E, Bateman DA. (2014). Normal levels of the antiprion proteins Btn2 and Cur1 cure most newly formed [URE3] prion variants. Proc Natl Acad Sci USA. 111(26):E2711-E2720

Gorkovskiy A, Reidy M, Masison DC, Wickner RB. (2017). Hsp104 disaggregase at normal levels cures many [PSI+] prion variants in a process promoted by Sti1p, Hsp90 and Sis1p. Proc Natl Acad Sci USA. 114(21):E4193-E4202