Page 17 - Rappaport Institute Magazine 2024

BIOCHEMISTRY
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Protein Homeostasis Regulatory Networks – function and malfunction during stress and in neurodegeneration
The Shalgi lab undertakes a systems biology approach, integrating transcriptomics, high throughput screens, molecular and computational biology, to unravel novel features of protein homeostasis (proteostasis) regulation. Using a novel screening approach for modulators of pathological aggregation, we revealed specialized chaperone requirements of ALS-associated FUS aggregation (Rozales et al. Nat Comm 2022). Currently, the lab is pursuing a novel drug which we discovered to specifically target ALS-FUS aggregation. Furthermore, we broadened the view of chaperone networks combinatorial regulation, by revealing differential roles for chaperone isoforms in regulation of pathological aggregation. Current projects in the lab take a systematic approach to further characterize chaperone networks combinatorial regulation. Additional projects employ high-content live imaging and image analysis to characterize the dynamics and regulation of stress granules in normal stress biology, and their aberrations in Huntington’s disease. Together, we strive to broadly understand system-level features of proteostasis networks to understand how they function in maintaining proteostasis under fluctuating environments, and uncover how they malfunction in disease in order to battle neurodegeneration.
Selected Publications
ˆ Rozales, K.*, Younis, A.*, Saida, N., Meller, A., Goldman, H., Kellerman, L., Heinrich, R., Berlin, S., Shalgi, R. (2022) Differential roles for DNAJ isoforms in HTT- polyQ and FUS aggregation modulation revealed by chaperone screens. Nat Commun 13, 516.
• Picked to feature in the Editor’s Highlights page of Nature Communications.
ˆ Hadar S, Meller A, Saida N, Shalgi R. (2022) Stress-induced transcriptional readthrough into neighboring genes is linked to intron retention. iScience 25, 105543. ˆ Sabath, N.*, Levy-Adam, F.*, Younis, A.*, Rozales, K., Meller, A., Hadar, S., Soueid- Baumgarten, S., Shalgi, R. (2020) Cellular proteostasis decline in human senescence. *Equal contribution. PNAS. 117(50):31902-31913.
• Highlighted in Communications Biology: Montague-Cardoso K (2021) Cellular proteostasis decline in human senescence. Communications Biology 4(1):17. https:// www.nature.com/articles/s42003-020-01578-w
Grants and Awards
2016 – Alon Fellowship for Outstanding Young Researchers, Council for Higher Education, Israel
2016 – ERC Starting Grant
2022 – Crown Vanguard Award for Science and Technology, Technion
2023 – The Rechler Prize for Excellence in Research, Technion
2023 – RTICC Research Award 2022, Technion Integrated Cancer Center
2023 – US Department of Defense (CDMRP) ALS Therapeutic Idea Award Collaborators
Prof. Joan Steitz, Yale School of Medicine. Collaborative paper in PNAS:
Vilborg, A., Sabath, N., Wiesel, Y., Nathans, J., Levy-Adam, F., Yario, T.A., Steitz, J.A., Shalgi, R. (2017). Comparative analysis reveals genomic features of stress-induced transcriptional readthrough. Proc Natl Acad Sci U S A 114, E8362-E8371
reutshalgi@technion.ac.il
Reut Shalgi Lab
Reut Shalgi, PhD
Associate Professor of Molecular and Systems Biology
PhD, 2009 – Weizmann Institute of Science, Israel
Cells expressing the protein FUS with an ALS-causative mutation (green). This protein generates aggregates within the cells (white arrows). When the chaperone DNAJB14 (pink, right panel) is co-expressed together with mutant FUS, cells generate remarkably less FUS aggregates, and FUS remains largely diffused in the cells.