Cysteine modifications in aging and neurodegeneration?!!?!?

Who was I talking to the other day at length about cysteine modifications? Somebody locally here in Maryland. I have the vague impression I felt outclassed intellectually, but that doesn't really narrow it down too much...

Eons ago, I was involved in a study where normal shotgun proteomics techniques totally messed up our work. We were studying a compound and it caused big protein mass shifts if you incubated it with a single or a mix of proteins, but we couldn't find peptide mass shifts. Turned out that the compound loosely bound to cysteines and when we reduced and alkylated the iodoacetamide displaced the compound. (We weren't reducing and alkylating the intact proteins; just shooting them intact). I've always wondered since then if we are losing other information about cysteines by using these techniques.

(Side note: it is a very common practice in big Pharma companies I've visited that are studying antibodies for them to do a digest of their antibody with and without reducing and alkylating and most of their software can take both runs and make conclusions about what the cysteines are doing)

Want to worry more about cysteine states?  Check out the study in the screenshot above (link here)!  Maybe this is all stuff you already know that I don't, but this review matter-of-factedly states all sorts of stuff about cysteine PTMs that I knew nothing about until this morning.

It is well established that cysteine oxidation is linked to aging (what?!?) cause the redox stuff that cysteine does that is critical to many protein functions is inhibited by the build up of modifications on it (??).  But not very much is known about what specific PTMs or patterns of PTMs are the most critical.

I DON'T EVEN LOOK FOR CYSTEINE PTMS!  And they talk about 8!!! reversible cysteine PTMs that play really key roles in cellular regulation and stuff that I probably can't see cause I've blasted all my cysteines with a crazy strong reducing agent and then bound something to them.

However, all is not lost --- this paper discusses the established techniques for going after these PTMs. By using alternative reduction techniques or even modifying the PTMs themselves, you can study the changes in these -- and even, in some cases, directly enrich for peptides with this cysteine modification state.

Each one appears highly involved, but if you are sitting there looking at a phenotype that you can't explain from a global proteome level, maybe this is something to go after?  I doubt you could find a more definitive review on this topic!