Registrations are due March 10, and both travel grants and dependent care grants are available. We look forward to seeing you in Portugal next summer!

meetings.embo.org/event/26-rna...

Thanks Junjie!

Thanks Mike! I looked into this a while back, and I am a direct patrilineal descendant of this guy: www.findagrave.com/memorial/133.... Blacksmithing skills got lost somewhere along the way though.

www.biorxiv.org/content/10.1...

Thanks Manny!

www.biorxiv.org/content/10.1...

...the unnecessary loss of time, expertise, and money. In short, it is the opposite of increased efficiency.

...from the people in the lab doing the experiments to the staff that oversee compliance with regulations to ensure thoughtful stewardship of hard earned taxpayer money. Wild, unpredictable changes to the system result in turnover of these key personnel, resulting in...

Finally, one more comment given recent events. All this work, which may one day lead to cures for ALS, relies not just on federal funding, but on a *stable* funding system, including indirect costs. Those funds pay the salaries of people that are indispensable to this effort...

If we replace wildtype TDP-43 with an ALS mutant TDP-43, we again see that the same RNAs become aberrantly neurite-enriched. So this could be happening in ALS patient cells, but whether it makes contributions to patient phenotypes is another question for another day.

Does any of this have anything to do with ALS? Maybe. We see the same RNA localization defects happening in primary mouse motor neurons and human iPS-derived motor neurons upon TDP-43 loss.

260mers that drove TDP-43-dependent localization and were bound by TDP-43 in vitro also showed TDP-43-dependent changes in stability, directly linking all three processes. All of these qualities were eliminated if TDP-43 motifs in the 260mers were eliminated.

OK, so *how* is TDP-43 doing this? TDP-43 negatively regulates RNA stability and recent work has linked RNA localization and stability. So is this what's going on? To test this we measured the stability of the same ~10k reporters with and without TDP-43 using SLAM-seq.

Sure enough, 260mers that have TDP-43-dependent localization activity are directly bound by TDP-43, and mutation of TDP-43 motifs within them abrogates both binding and activity.

OK so we have 260mers that have TDP-43-dependent RNA localization activity. But are they actually bound by TDP-43? To test this, we measured the TDP-43 affinity for the exact same ~10k 260mer RNAs in vitro, allowing us to directly relate binding to activity.

So what distinguishes these bound/active motifs from unbound/inactive motifs? Secondary structure. Bound motifs are significantly more single-stranded. We can predict whether or not a TDP-43 motif regulates RNA localization simply by looking at its secondary structure character.