"Amyloid-motif-dependent tau self-assembly is modulated by isoform sequence context"

Free access: authors.elsevier.com/c/1mDc93SNvc...

… unless you’ve heard me talk about it, which I’ve done a lot over the past decade :D Including in this Quanta video: youtu.be/KDQFUmDJ3nY?...

But now this project is finally preprinted!! The answer is skin cells. Skin cells!
www.biorxiv.org/content/10.1...

I’m very grateful to all the wonderful people who contributed to this project. Working with them was an absolute pleasure.

B) Maybe not physiologically relevant, but (weirdly) heparin-incubated DnaJB1 assumes ThT-positive conformations, and we confirmed this formation of larger entities with other techniques. What monster did we create out of this molecular chaperone?! To be confirmed.

There's much more in this paper, so check it out. There’s A LOT of cool stuff in the supplementary figures too! For example, A) DnaJB1 knockdown in our cell model of alpha-synuclein aggregation increases inclusion formation by 40%. Previously, a complete knockout of this chaperone showed no impact.

So, we provide another evidence that charge distribution of the misfolded client is crucial for chaperone recognition. IMO it would be super interesting to check if the pathology-associated phosphorylation of tau impacts how other cellular factors interact with these tau species.

Many studies investigating chaperones’ role on tau aggregation have used this model. With this work, we want to signal that this HUGELY changes the nature of chaperone-tau interactions.

HOWEVER, it is now known that heparin-made tau fibrils are structurally very different from any patient-derived tau fibrils.

A huge caveat while working on tau aggregation is that (quite ironically huh) this protein is incredibly soluble and to induce its fibrilization we often need to mess with the buffer composition or add external factors, like polyanionic heparin.

This chaperone seems to recognize short acidic sequences located on this part of tau. And together with the weak, transient nature of these interactions, it looks like our results fit nicely with what was reported for alpha-synuclein.

Using in vitro and cell models of tau aggregation we found that DnaJB1 can inhibit tau aggregation by recognizing its N-terminal part which remains disordered and, quite crucially, makes a solvent-accessible ‘fuzzy coat’ along tau fibrils.

We investigated how this chaperone binds to tau protein. Tau's aggregation has been connected to Alzheimer’s disease, FTD, and others. We were strongly inspired by what was found previously for this chaperone in the context of alpha-synuclein (but also super important early in vitro work on tau!!).

How organism’s protein quality control recognizes and binds to such protein species looks like an important research question, doesn’t it? Here, we focused on a specific member of this network, a Hsp70’s co-chaperone – DnaJB1 (it’s a J-domain protein, you may also know this protein family as Hsp40s)

Protein misfolding may lead to emergence of deposits of aggregated proteins, with the most infamous example of the amyloid fibrils found in brains of patients diagnosed with neurodegenerative diseases.