A recent article from STAT news (1) relayed the story of Jaci, a young woman in Iowa dying from a rare form of ALS, and her parents heroic efforts to help her get access to an untested drug.
Interestingly, the drug is an antisense oligonucleotide. Antisense oligos are short pieces of DNA, that bind to complementary molecules of mRNA and target them for destruction. These types of drugs are interesting because they can prevent the production of toxic proteins.
In Jaci’s case, her form of ALS results from a toxic version of the FUS protein. Normally, FUS is found in the nucleus of a cell working to regulate RNA production. FUS also plays a role in splicing RNA and transporting it out of the nucleus. Jaci’s mutation changes the FUS protein so that a proline at position 525 gets replaced with a different amino acid, a leucine.
Why is Pro525leu a problem?
Well, remember a few sentences ago, I wrote that FUS normally hangs out in the nucleus and works on RNA?
As it often happens in biology, FUS can’t get across the nuclear membrane without a little help from a friend. This friend is an importin protein named Karyopherin-ß2 (or transportin-1) (2). I’ll call it “Kary” for short because these crazy protein names are too hard to pronounce.
Anyway, FUS needs Kary’s help if it’s going to travel across the nuclear membrane and transport RNA.
If we look at the normal interaction between FUS and Kary in 5YVI, we can see where P525 normally fits in with Kary.
Here’s what it looks like if we zoom in and color the PY sequence in FUS by hydrophobicity. PY is a nuclear localization signal, like an address, that tells Kary to put FUS in the nucleus.
If that P525 is replaced with a leucine, as it is in Jaci, that tight binding is prevented. Leucine is longer than proline and the leucine sidechain pushes Kary away.
When the Pro525leu mutation is present, the PY nuclear localization signal in FUS is pushed away, so Fus doesn't to Kary quite so snugly. When FUS can’t go to the right place in the cell, it ends up forming clumps. An increase in clumps is associated with more severe ALS.
If the experimental drug can prevent this toxic FUS protein from being made, Jaci's situation might improve.
Nicholas Florko, When ‘right to try’ isn’t enough: Congress wants a single ALS patient to get a therapy never tested in humans STAT news May 31, 2019
Yoshizawa T, Ali R, Jiou J, Fung HYJ, Burke KA, Kim SJ, Lin Y, Peeples WB,Saltzberg D, Soniat M, Baumhardt JM, Oldenbourg R, Sali A, Fawzi NL, Rosen MK, Chook YM. Nuclear Import Receptor Inhibits Phase Separation of FUS through Binding to Multiple Sites. Cell. 2018 Apr 19;173(3):693-705.e22. doi:10.1016/j.cell.2018.03.003.