About the Project
Our lab studies stress signaling and pioneers strategies that harness such pathways to enhance cellular resilience, a modality generically applicable to improve fitness in diverse diseases, including the age-related neurodegenerative diseases.
Neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and Amyotrophic Lateral Sclerosis (ALS) are clinically different yet share a common molecular aetiology. These diseases are caused by the progressive dysfunction and death of nerve cells in selective regions of the brain due to the accumulation of certain proteins in the form of insoluble assemblies. Cells normally strive to ensure that proteins get correctly folded, relying on powerful and sophisticated protein quality control systems to protect against the potentially harmful proteins they produce all the time.
We design powerful strategies that harness stress signaling to boost cellular resilience to misfolded proteins and protect from different neurodegenerative diseases. Some of the small molecules we reported are tested in human clinical trials: Guanabenz was found to be efficacious in a Phase 2 trial in ALS and Phase 2 trials are ongoing with Sephin1, after successful Phase 1 and Phase 2a trials.
Our work is pluridisciplinary by nature, combining chemistry, biochemistry, biophysics, structural biology and cell biology with mouse models of diseases. Our work is led by curiosity and is data-driven. Our goal is to solve big fundamental problems that will ultimately improve human health.
Various projects are available. Two projects will focus on characterising novel regulatory mechanisms governing components of the integrated stress response (ISR) using a combination of cell biology, biochemistry, genetics, and proteomics. Other projects will investigate the structural basis of key components of the integrated stress response through biochemical approaches, structural proteomics, and cryo-electron microscopy (cryo-EM).
References
Tsaytler et al., 2011, Science, 332, 91-4; Das et al., 2015, Science, 348, 239-242; Carrara, M., Sigurdardottir, A., & Bertolotti, A. 2017, Nat Struct Mol Biol; Krzyzosiak, A., Sigurdardottir, A. et al., A. 2018, Cell; Szaruga M, et al,. Nat Commun, 2023. 8;14(1):5535; Fatalska A., Hodgson G, et al., Mol Cell. 2024. De Miguel C, et al,. Science. 2026.