Agnieszka Krzyżosiak

Enhancing cellular proteostasis as a strategy against misfolded proteins accumulation

Abstract

Neurodegenerative diseases (NDDs) are devastating, age-related disorders, which despite substantial efforts remain largely uncurable. The incidence of NDDs rises dramatically in our aging population, which points to an urgent need to tackle these fatal diseases. The deposition of misfolded proteins in a cell is a defining feature of NDDs that points to the deregulation of protein quality control (PQC) pathways in NDDs. With that said, enhancing the PQC systems could serve as an attractive therapeutic strategy.

We have validated this concept by identification of PQC-boosting selective phosphatase inhibitors. These eIF2a pathway-targeting small molecules readily crossed the blood-brain barrier and were safe upon chronic administration in vivo. Enhancing cellular proteostasis using those agents prevented the behavioral and molecular deficits in NDD mouse models as well as prevented neurodegenerative phenotypes development in human reprogrammed neurons, derived from patients by direct conversion of fibroblasts, a model retaining the genetic and epigenetic background of the disease.

The beneficial effect of boosting PQC was recapitulated upon genetic manipulation of the pathway. This work demonstrates the disease-modifying potential of phosphatase inhibitors and points to the opportunities to identify therapeutic targets in neurodegeneration within the space of the protein quality control.

Biography

Agnieszka Krzyżosiak, Ph.D. – Head of the Laboratory of Mechanisms of Neurodegeneration at Łukasiewicz – PORT from February 2023.

Agnieszka completed her Ph.D. research at The Institute of Genetics and Molecular and Cellular Biology (IGBMC) in Strasbourg, France and received her cotutelle Ph.D. at the Louis Pasteur University in Strasbourg and Wrocław University of Science and Technology. She next accomplished the EMBO and HFSP funded postdoc at the Medical Research Council Laboratory of Molecular Biology (MRC LMB) in Cambridge, UK followed by the translational development of her scientific research in a spinoff biotech startup.

“Agnieszka’s lab is interested to understand how protein quality control (PQC) deregulation contributes to neurodegeneration. In her research, together with her colleagues, Agnieszka showed that PQC can be targeted for the therapeutic benefit against protein accumulation – an approach currently developed clinically. Building on that, with the use of patient-derived models, the aim of the lab is to scrutinize the PQC pathways in neurodegeneration in the aim to identify novel treatment strategies.”