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.

References

Selective inhibition of a regulatory subunit of protein phosphatase 1 restores proteostasis.
Tsaytler P, Harding HP, Ron D, Bertolotti A
Science 332(6025): 91-4 (2011)

Preventing proteostasis diseases by selective inhibition of a phosphatase regulatory subunit.
Das I, Krzyzosiak A, Schneider K, Wrabetz L, D’Antonio M, Barry N, Sigurdardottir A, Bertolotti A
Science 348(6231): 239-42 (2015)

Decoding the selectivity of eIF2α holophosphatases and PPP1R15A inhibitors.
Carrara M, Sigurdardottir A, Bertolotti A
Nat Struct Mol Biol 24(9): 708-716 (2017)

Target-Based Discovery of an Inhibitor of the Regulatory Phosphatase PPP1R15B.
Krzyzosiak A, Sigurdardottir A, Luh L, Carrara M, Das I, Schneider K, Bertolotti A
Cell 174(5): 1216-1228.e19 (2018)

Activation of the integrated stress response by inhibitors of its kinases.
Szaruga M, Janssen DA, de Miguel C, Hodgson G, Fatalska A, Pitera AP, Andreeva A, Bertolotti A
Nat Commun 14(1): 5535 (2023) Epub

Recruitment of trimeric eIF2 by phosphatase non-catalytic subunit PPP1R15B.
Fatalska A, Hodgson G, Freund SMV, Maslen SL, Morgan T, Thorkelsson SR, van Slegtenhorst M, Lorenz S, Andreeva A, Kaat LD, Bertolotti A
Mol Cell 84(3): 506-521.e11 (2024)