Steven Boeynaems, PhD
Assistant Professor - Department of Molecular and Human Genetics, Baylor College of Medicine
Investigator - Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital
Faculty Member - Center for Alzheimer’s and Neurodegenerative Diseases (CAND), Therapeutic Innovation Center (THINC), Dan L. Duncan Comprehensive Cancer Center (DLDCCC)
The overall focus of our lab is to understand one of the most basic questions in biology: how do cells perceive and deal with stress? Stress is a universal feature of all cellular Life. Whether it concerns abiotic (e.g., temperature) or biotic (e.g., viral infection) stress, cells/organisms need to adapt to their ever-changing environment. Protein aggregation is a hallmark of a stressed cell, so how do cells protect themselves? It is becoming increasingly clear that cells undergo broad (reversible) spatial and biophysical rearrangements of their entire proteome in times of stress, yet the regulatory and organizational principles remain almost completely unresolved. Biomolecular condensates (BMCs) have emerged as key stress-responsive compartments, and our work has indeed shown that such assemblies allow cells to sense and respond to stress.
Protein aggregation and the stress response are intimately tied to human disease. They span a large range - from age-related stresses or exposure to environmental/physical stresses in neurodegenerative disease, the cellular stress caused by hypoxia and chemotherapy in the tumor microenvironment to the corruption of the host proteostatic machinery in infectious disease. Stress and the associated responses modulate the onset and progression of virtually every human disease. It therefore may come as no surprise that defects in BMCs are associated with several human diseases and the aging process. Yet, we still have a very limited understanding whether such BMC alterations are adaptive or actually driving dysfunction, and whether we can drug them. Our lab addresses this open question by using a multidisciplinary approach—spanning biophysics to in vivo modelling and drug screening—combined with orthogonal model systems and a synthetic biology tool kit to untangle how the biophysical stress response is regulated and to engineer new tools to therapeutically target it in aging and human disease.
We mostly focus on neurodegenerative diseases and brain cancer, but understand that the same molecular processes underlying these conditions are not exclusively limited to humans. Indeed, evolution has already found solutions to many of the problems we face in human medicine today. For example, while the aging human brain is incredibly susceptible to protein aggregation, other organisms seem to defy the biological limits of life and are able to maintain proteostasis in the harshest of environments. It is therefore that we are teaming up with collaborators from around the world to study stress-tolerant organisms to understand the molecular underpinnings of their resilience. Figuring out how these organisms prevent proteins from aggregating will highlight new strategies to boost proteostasis in protein aggregation diseases. In all, a multi-model and evolution-inspired approach forms the backbone of our lab. By repurposing Nature’s ingenuity, we develop innovative bio-synthetic and -mimetic tools and drugs to combat disease.
Selected publications [* indicates co-first authors]:
- Lasker K*, Boeynaems S*, Stainton E, Jacquemyn M, Daelemans D, Holehouse A, Gitler AD, Shapiro L. A modular platform for engineering function of natural and synthetic biomolecular condensates. Nature Communications 2022, vol. 13, 5643. [PMID: 36163138]
- Dorone Y*, Boeynaems S*, Flores E, Jin B, Hateley S, Bossi F, Lazarus E, Pennington JG, Michiels E, De Decker M, Vints K, Baatsen P, Bassel GW, Otegui MS, Holehouse AS, Exposito-Alonso M, Sukenik S, Gitler AD, Rhee SY. A prion-like protein regulator of seed germination undergoes hydration-dependent phase separation. Cell 2021, vol. 184(16), p. 4284-4298. [PMID: 34233164]
- Hasting RL and Boeynaems S. Designer condensates: a toolkit for the biomolecular architect. Journal of Molecular Biology 2021, vol. 433(12), 166837. [PMID: 33539874]
- Fumagalli F*, Young FL*, Boeynaems S*, De Decker M, Mehta A, Swijsen A, Fazal R, Guo W, Moisse M, Beckers J, Dedeene L, Bhuvaneish TS, Vandoorne T, Madan V, van Blitterswijk M, Raitcheva D, McCampbell A, Poesen K, Gitler AD, Koch P, Vanden Berghe P, Thal DR, Verfaillie C, Chandran S, Van Den Bosch L, Bullock S, Van Damme P. C9orf72-derived arginine-containing dipeptide repeats associate with axonal transport machinery and impede microtubule-based motility. Science Advances 2021, vol. 7(15), eabg3013. [PMID: 33837088]
- Fazal R, Boeynaems S, Swijsen A, De Decker M, Fumagalli L, Moisse M, Vanneste J, Guo W, Boon R, Vercruysse T, Eggermont K, Swinnen B, Beckers J, Pakravan D, Vandoorne T, Vanden Berghe P, Verfaillie CM, Van Damme P. HDAC6 inhibition restores TDP-43 pathology and axonal transport defects in human motor neurons with TARDBP mutations. The EMBO journal 2021, vol. 40, e106177. [PMID: 33694180]
- Tazelaar GHP*, Boeynaems S*, De Decker M*, van Vugt J, Kool L, Goedee HS, McLaughlin RL, Sproviero W, Moisse M, Jacquemyn M, Daelemans D, Dekker AM, van der Spek RA, Westeneng HJ, Kenna KP, Assialioui A, Da Silva N, Project MinE ALS Sequencing Consortium, Povedano M, Hardiman O, Salachas F, Millecamps S, Vourc'h P, Corcia P, Couratier P, Morrison KE, Shaw PJ, Shaw CE, Pasterkamp RJ, Landers JE, Van Den Bosch L, Robberecht W, Al-Challabi A, van den Berg LH, Van Damme P, Veldink JH, van Es MA. ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization. Brain Communications 2020, fcaa064. [PMID: 32954321]
- Boeynaems S, Holehouse AS, Weinhardt V, Kovacs D, Van Lindt J, Larabell C, Van Den Bosch L, Das R, Tompa P, Pappu RV, Gitler AD. Spontaneous driving forces give rise to protein-RNA condensates with coexisting phases and complex material properties. PNAS 2019, vol. 116(16), p. 7889-7898. [PMID: 30926670]
- Bogaert E*, Boeynaems S*, Kato M, Guo L, Caulfield TR, Steyaert S, Scheveneels W, Wilmans N, Haeck W, Hersmus N, Schymkowitz S, Rousseau F, Shorter J, Callaerts P, Robberecht W, Van Damme P, Van Den Bosch L#. Molecular dissection of FUS points at synergistic effect of low-complexity domains in toxicity. Cell Reports 2018, vol. 24(3), p. 529-537. [PMID: 30021151]
- Boeynaems S, Alberti S, Fawzi NL, Mittag T, Polymenidou M, Rousseau F, Schymkowitz J, Shorter J, Wolozin B, Van Den Bosch L, Tompa T, Fuxreiter M. Protein phase separation: a new phase in cell biology. Trends in Cell Biology 2018, vol. 28(6), p. 420–435. [PMID: 29602697]
- Boeynaems S, Bogaert E, Kovacs D, Konijnenberg A, Timmerman E, Volkov A, Guharoy M, De Decker M, Jaspers T, Ryan VH, Janke AM, Baatsen P, Vercruysse T, Kolaitis RM, Daelemans D, Taylor JP, Kedersha N, Anderson P, Impens F, Sobott F, Schymkowitz J, Rousseau F, Fawzi NL, Robberecht W, Van Damme P, Tompa P, Van Den Bosch L. Phase Separation of C9orf72 Dipeptide Repeats Perturbs Stress Granule Dynamics. Molecular Cell 2017, vol. 65(6), p. 1044-1055. [PMID: 28306503]