Official student-run #ScienceTwitter of the Jackrel Lab at WashU/STL. Studying the biochemistry of protein misfolding, chaperones, & disaggregases
St. Louis, MO
Joined July 2018
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We are excited to share our paper on Matrin-3 phase separation that is out now!
Online Now: Matrin-3 forms spherical and wormlike assemblies that are modulated by RNA binding and ALS/FTD-associated mutations dlvr.it/TNDLRP
Jackrel Lab Members retweeted
Grateful for a 5-yr R01 award from the National Institute on Aging for developing vaccines against neurodegenerative diseases. Thanks to collaborations with @JackrelLab and support from @WashUBME @WashUengineers
Jackrel Lab Members retweeted
Interesting: New paper from @JackrelLab & colleagues reports PDZ serine protease HTRA1 disaggregates #Parkinsons-associated α-synuclein amyloid fibrils & converts them into non-toxic/seeding incompetent species; Future = small molecule HTRA1 modulators
nature.com/articles/s41467-0…
Check out the paper now to get all the juicy🧃details! nature.com/articles/s41467-0…
Big shout out 🗣️ to the team that made it all possible: Sheng Chen, @AnuradhikaP, Braxton Bell, Joey Fritsche, Hector Palacios, Maurie Balch, @MacySprunger, @matthewkhoward, Jeremy Ryan, Jessica Haines, @gjpattij, @GusDavisLab, & Meredith Jackrel!
8. Finally, we found that aSyn remodeled by HTRA1 is non-toxic and incapable of seeding the formation of pathological aSyn inclusions in primary hippocampal neurons from mice. 🐭
7. Through genetic approaches, we found that overexpression of HTRA1 can prevent aSyn seeding aggregation while reducing HTRA1 promotes aSyn seeding aggregation. ↕️
6. Mass spectrometry analysis of HTRA1 proteolysis toward aSyn fibrils reveals that HTRA1 cleaves the NAC domain at the core of aSyn fibrils via the HTRA1 protease domain. This suggests that HTRA1 remodeling of aSyn fibrils makes the NAC domain accessible. ✂️
5. Beyond inhibiting aggregation of aSyn, we found that HTRA1 is also active against pre-formed aSyn fibrils. HTRA1 can disaggregate and solubilize aSyn pre-formed fibrils in a proteolytically-independent manner, generating a cell seeding-incompetent form of aSyn. 🦠
4. Domain mapping of HTRA1 revealed that the protease domain of HTRA1, but not its proteolytic activity, is responsible for the chaperone activity against aSyn. The PDZ domain of HTRA1 is dispensable for its activity. 🧩
3. Treating a HEK293T aSyn FRET cell model with exogenous aSyn fibrils results in intracellular aSyn fibrillization measurable by FRET.💡However, we found that forming the exogenous aSyn fibrils in the presence of HTRA1 prevents the seeding of intracellular aSyn fibrillization.
2. Our biophysical characterization of HTRA1 reveals that it can prevent amyloidogenesis and preserve solubility of both wild-type aSyn and its familial Parkinson’s disease🤕mutation A53T. Yet again, we found that this activity is independent of HTRA1 proteolysis activity!
1. We observed that HTRA1 and HTRA2 serine proteases selectively proteolyze disordered proteins, (aSyn, TDP-43, and FUS), but not well-folded proteins (MBP and GST). Surprisingly, HTRA1 inhibits TDP-43 and FUS aggregation in a protease-independent manner! ✂️🚫
📢We are excited to share that our paper on HTRA1 remodeling of alpha-synuclein is available now online with @NatureComms! Check out our main findings below 👇
So happy for and proud of our favorite boss Dr. Jackrel! Newest tenured prof in @WashUChem!
Yesterday Sheng (Andy) Chen defended his dissertation like a star ⭐️ We are proud of all he has accomplished during his graduate studies! Congrats Dr. Chen!
Yesterday we celebrated @MacySprunger's dissertation defense! 🎉She is the first graduate student to defend from the lab and we are very proud of all she has accomplished during her graduate studies!🧬
It is the first look at one of our big projects in the lab! We have been investigating how human serine protease HTRA1 can prevent and disaggregate alpha-synuclein amyloid! You can check out the preprint now 👇👇researchsquare.com/article/r…