New preprint alert! Steven's paper on ATXN2 hits BioRxiv! This one has been in the making for quite some years and really took a village to pull off. We uncovered that poly(A)-binding proteins (PABPC) moonlight as protein chaperones. They bind to a short linear motif (SLiM) in ATXN2's C-terminal disordered tail hereby (1) preventing its spontaneous condensation under normal conditions, and (2) driving its recruitment into stress granules. We followed up on this observation by showing that this condensation switch is functionally conserved across eukaryotes. Additionally we use designer condensates and engineered versions of PABPC to figure out the cis and trans interactions that mediate its new function. PABPCs are such well-studied proteins so it is super exciting that we found this novel ancient function for them. A better understanding of this chaperone circuit is giving us some new ideas on how their interaction may be implicated in ALS and SCA. Lastly, we think that SLiMs may be an underexplored way of how biomolecular condensates regulate their composition, and we are thinking of ways on how to develop our designer condensates in tools for high-throughput discovery. Lots of stuff to follow up on... Check out the preprint for more details!
Steven provided cover art for the latest edition of Cell to accompany the FLOE1 paper: "Water is essential to all Life. Yet, numerous organisms have evolved strategies to cope with drought and water shortages. Plant seeds are specialized propagation vectors that use desiccation to protect the embryo in a quiescent state that can remain viable for years to millennia. Hydration of the seed is the key environmental trigger for metabolic reactivation, preceding germination. However, the mechanism by which seeds can sense water availability remained unresolved. Dorone and Boeynaems et al. (4284–4298) discover a novel prion-like protein in Arabidopsis that regulates the germination rates in conditions of low water availability by acting as a seed’s water sensor. Cover design: “Cellular deserts” by Steven Boeynaems depicts a surrealist interpretation of a desiccated plant embryo based on a confocal 3D reconstruction of an Arabidopsis embryo".
Yanniv and Steven's collaborative paper is finally out in Cell ! Big thanks to all collaborators, ADG and Sue Rhee. This one really took a village. In brief, we discovered an unknown gene, FLOE1, in plants that acts as a seed's water sensor by undergoing a reversible hydration-dependent phase transition. Moreover, we see evidence in wild populations that natural variation in this gene is correlated with germination characteristics and tuned to the local climate. This finding has big implications for the development of designer crops, especially in light of climate change.
New paper out with Lane Baker and Alicia Friedman in Analytical and Bioanalytical Chemistry. We created synthetic mimics of the nuclear pore complex to test the effect of C9orf72 DPRs on pore permeability. Super simple model system that will definitely be useful to test atomistic interactions in other biomolecular phases.
Steven's artwork made it to the cover of the special issue on phase separation at Journal of Molecular Biology! Go check out this fantastic issue with so many exciting reads, including our FASE manuscript.
Another collaborative paper with the Van Damme, Van Den Bosch and Bullock labs got published at Science Advances. Together with Laura Fumagalli and Florence Young, we uncovered axonal transport defects as a novel pathogenic mechanism in C9orf72 ALS/FTD. By combining in vitro and cellular transport assays, phase separation assays, in vivo modeling, and human pathology data, we show that arginine-rich repeat peptides poison microtubule-based transport. These findings further implicate axonal transport defects in the pathogenesis of ALS/FTD and point at new therapeutic approaches.
Our collaborative paper with the Van Damme and Van Den Bosch labs got published at the EMBO Journal. Raheem Fazal spearheaded this project where we find using patient-derived IPSC motor neurons that mutant TDP-43 induces axonal transport defects. Excitingly, all pathological TDP-43 features (nuclear depletion, solubility, cleavage, and hyperphosphorylation) and the defective axonal transport were corrected by treatment with HDAC6 inhibitors. These findings indicate that (1) mutant TDP-43 are a good preclinical model of the early steps of ALS/FTLD pathogenesis, and that (2) HDACi could be a promising therapeutic option for cases with TDP-43 pathology, which present the majority of the entire disease spectrum.
Keren and Steven submitted their collaborative paper on the PopZ project. You can find the manuscript on BioRxiv. In brief, we find that the material properties of a bacterial biomolecular condensate tune organismal fitness in a non-linear manner, and find evidence suggesting selection on sequence properties that can fine-tune the material state to the environmental niche. Additionally, based on the modular domain architecture of PopZ, we engineered a novel platform for the generation of an unlimited variety of designer condensates for use in prokaryote and eukaryote systems.
Renee and Steven had their invited review for the JMB special issue on phase separation accepted! We review the recent efforts in the field regarding the generation of "designer condensates". To give it our personal twist, we made all of the figures in the style of IKEA manuals to inspire researchers to start playing with phase separation building blocks and come up with their own designer condensates. We also created a website with a useful design manual and info on all the building blocks. Check it out at www.designercondensates.org!
Out of ~1,800 applicants, Anushka is one of 40 Regeneron finalists! So well-deserved and immensely proud as a mentor. Anushka wowed the judges with her work on novel RNA-based strategies to target TDP-43 in neurodegenerative disease.
Steven gave a talk on novel tools to generate designer condensates at New York University. Thanks to Liam Holt for the invite, and everyone for the lengthy Q&A session. Had so much fun!
Wishing all of you an exciting and fulfilling 2021!
IDPSIG and IDPseminars had a fantastic joint holiday bash. It was great to turn the tables and let all the organizers present. Amazing to be able to give a talk in such a stellar line up of early career scientists. Thanks everyone for attending and supporting us. Steven talked on the discovery of an unconventional chaperone that regulates ATXN2 and its implication in spinocerebellar ataxia.
Steven talked at the VIB phase separation workshop about combining mass spec and machine learning approaches to uncover novel proteins and biological processes implicating phase separation. Great discussion and it was fun to see many familiar faces. Thanks to Thomas Moens and Eleonora Leucci for inviting me!
Steven his submission for the 2020 NanoArtography competition got 2nd place! Super honored to be featured among all those great science artists with wonderful submissions from all over the world.
Steven gave a talk at the Center for Nanoscience at at the Ludwig-Maximilians-University (LMU) in Munich, Germany. He talked on how phase separation allows organisms to encode biological function. Thanks to everyone for the awesome discussion and specifically to Jan Lipfert and Willem Vanderlinden for hosting me. Had a great time. Hope to see you all soon irl!
Steven joined a career panel discussion for junior neuroscientists at the AAIC organized by the Alzheimer's Association. Was great to discuss career paths and answer questions of graduate students on how to navigate the academic job market.
Steven gave a talk at the department of Molecular Biology at the University of Wyoming. Talked on how phase separation is implicated in numerous ways in the (a)biotic stress response in a wide variety of organisms. Really enjoyed the Q&A session with only grad students and answer both their scientific and career path questions. Thanks all for the warm welcome, and hope to visit soon. Special thanks to Thomas Boothby for inviting me. It was an honor and pleasure!
Steven gave a guest seminar on neurodegenerative diseases at the UNIFESP in São Paulo, Brazil. One hour lecture with a 1.5 hour Q&A session. Was blown away by all the super insightful questions from the undergrad/grad students. The future of Brazilian neuroscience is looking bright! Thanks to Mirian A. F. Hayashi and Lucas Porta for inviting. Great experience!
More writing and trying to make too many deadlines. Some fun projects in the pipeline. Stay tuned!
Yanniv and Steven finally have the preprint of their collaborative paper online! Great collaboration with many people involved. Thanks to the Rhee lab for involving us in this awesome project, and thanks to the Holehouse and Sukenik labs, and my former mentees Emiel Michiels and Mathias De Decker for all the help. Really excited about this one! Read it on BioRxiv. TL/DR: We identified a previously uncharacterized gene family in plants that acts as a phase separation-based water sensor regulating seed germination. We called the gene FLOE1 after the second movement of Glassworks by Philip Glass. We show that phase separation and the exact material properties of the condensates are important for function in vivo, and some of our mutants have highly desirable agricultural traits. We strongly believe that such insights will help us generate designer crops to better withstand the effects of climate change.
Steven has been spending his pandemic days writing, writing and writing. Stay tuned!
Steven paid a virtual visit to St Jude Children's Research Hospital. Fantastic to catch up with old friends and hear all about the exciting research going on at the Department of Structural Biology and Department of Cell and Molecular Biology. Steven presented on how combining machine learning with novel mass spec approaches may help us uncover new phase separation biology and targets for age-related disease. Thanks to everyone for the warm welcome and specifically to J. Paul Taylor for hosting me.
Together with Gijs Tazelaar and Mathias De Decker we got our paper out on the role of ATXN1 in ALS. Analyzing around 11,700 individuals let us to conclude that intermediate CAG expansions in ATXN1 are associated with an increased risk for ALS. Based on data from cell culture and Drosophila models we hypothesize that ATXN1 may be implicated in the age-related misregulation of TDP-43. Lots of follow-up work to do to figure this out in detail! These findings as well strengthen the evidence for a growing overlap between ALS and SCA, and the role for repeat expansions in ALS. This was a fantastic collaboration with the Project Mine Consortium. Read the paper here at Brain Communications.
Anushka Sanyal is unstoppable!!! Not only did she and her twin brother make the local news with both their wins in the Synopsys science fair, but she also won the 2nd prize of the BioGENEius Bay Area regional competition. Congrats Anushka!
Anushka Sanyal, my high school student, was named a Grand Prize Winner for the Synopsys science fair. She presented her fantastic work on the development of novel RNA-based strategies to counter TDP-43 aggregation in ALS. Congrats Anushka, well-deserved!
Amidst the COVID-19 crisis we decided to end experiments and close down the lab for at least 30 days to protect ourselves and put social distancing measures in place to slow down this outbreak. Hope all of you and your loved ones are safe. Take care of one another.
Lucas Porta from the Hayashi lab is visiting us for 2 months. Lucas obtained the competitive CAPES-PrInt grant from the Brazilian government to come and pursue experiments with Steven on the toxicity of venom peptides. Welcome Lucas!
Steven presented a poster at the yearly Packard ALS meeting. Was great to catch up with old and new friends! The meeting was followed by our second edition of the GMSH Retreat (Gitler-Myong-Shorter-Ha labs), this time at Johns Hopkins University. Fantastic group of scientists, great constructive feedback and good interactions. Super excited about new collaborative projects.
Anushka Sanyal ended her high school internship with Steven, and will present her work on the role of RNA in TDP-43 toxicity at several state and national science fairs. Good luck Anushka!
IDPSIG organized its first symposium to celebrate our 2 year anniversary. More than 120 participants from all major Bay Area institutes attended the meeting. Thanks to all invited and selected speakers, and poster presenters for sharing their exciting science!
Steven gave a talk on the role of phase separation in ALS and SCA at the Center for Brain & Disease Research at VIB-KU Leuven. Great to see some familiar faces and sit together with students and postdocs to hear all about the exciting research going on.
Our collaborative paper with the Isaacs lab is online at Acta Neuropathologica! Lauren Gittings found that symmetric dimethylation of GR is correlated with increased survival in C9orf72 patients. Such a protective role was further supported by our analyses indicating that dimethylation affects the phase separation capacity of GR and reduces its neuronal toxicity. We reported years ago that arginine methyltransferases are genetic modifiers of DPR toxicity in Drosophila. Good to see we now finally have convincing data from patients supporting this!
Steven talks to Alzforum about our recent work on nucleocytoplasmic transport defects in C9orf72 ALS/FTLD.
Our collaborative paper with the Bullock and Van den Bosch labs is online at BioRxiv! Was great to work together with Laura Fumagalli and Florence Young on this. We discovered that C9orf72 arginine-rich DPRs perturb axonal transport by directly engaging the microtubules and associated motor complexes.
Collaborative paper with the Van den Bosch lab is accepted at Scientific Reports! Congrats Joni Vanneste for all the hard work! We show that C9orf72 arginine-rich DPRs do not directly cause nucleocytoplasmic transport defects, but rather act indirectly via triggering the cellular stress response.
New website goes live!