Neurodegeneration Mechanisms Research Group

Cells have sophisticated systems for maintaining protein quality—mechanisms that detect misfolded or damaged proteins and dispose of them before they can cause harm. In aging cells, these systems begin to fail. Proteins accumulate in forms they should not take, aggregate where they should not, and trigger processes that gradually destroy neurons. This is the molecular foundation of diseases like Alzheimer’s, Parkinson’s, and Huntington’s.

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The Neurodegeneration Mechanisms Research Group studies exactly this failure: how protein quality control breaks down with age, which molecular actors are responsible, and whether those actors can be targeted therapeutically. The long-term goal is to translate findings from fundamental research into strategies for treating or preventing neurodegenerative diseases, including early diagnostic tools that could identify these processes before symptoms emerge.

The group connects two levels of analysis. At the molecular level, the team maps the specific enzymes, chaperones, and signaling pathways that regulate protein homeostasis in neurons. At the cellular and disease model level, they develop and validate human models—particularly iPSC-derived neurons—that can represent the disease state with sufficient accuracy to test therapeutic candidates.

Meet our team

Dr. Agnieszka Krzyżosiak

Leads research on molecular mechanisms of gene regulation and RNA biology, with a focus on translational control and disease-relevant regulatory pathways.

Dr. Ewa Mazurkiewicz-Stanek

The researcher’s profile is being prepared.

Dr. Ewa Mrówczyńska

Works on induced pluripotent stem cell (iPSC)–based disease models, using patient-derived cellular systems to study human pathology in vitro. Collaborates with ICM Paris and Erasmus MC.

Dr. Agnieszka Górska

Investigates mRNA metabolism and proteostasis, focusing on how cells regulate protein homeostasis through RNA-level control mechanisms.

Dr. Daria Hajka

Studies extracellular vesicles and brain cell energy metabolism, with an emphasis on intercellular communication and metabolic regulation in neural systems. NCN MINIATURA laureate (2025).

Dr. Rohit Shrivastava

Focuses on neurodegenerative disease mechanisms, particularly Huntington’s disease, working on therapeutic targets and biomarker discovery in translational neurobiology.

Monika Danielewicz

Works on laboratory infrastructure and experimental support systems, including cell culture maintenance, quality control, and operational workflows enabling research continuity.

Karolina Cierluk

The researcher’s profile is being prepared.

Research questions

How does the integrated stress response (ISR) contribute to neurodegeneration? The ISR is a cellular pathway that cells activate under stress to reduce protein production and restore homeostasis. In acute stress, this is protective. In chronic neurodegeneration, dysregulation of the ISR—particularly through phosphatases PPP1R15A and PPP1R15B—may tip the balance toward cell death.

Dr. Krzyżosiak’s work at the MRC Laboratory of Molecular Biology (Cambridge, UK) identified the first selective inhibitor of PPP1R15B, which showed beneficial effects in a Huntington’s disease model. Current work at P4Health extends this line of inquiry.

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What drives selective neuronal vulnerability? Not all neurons are equally susceptible to neurodegeneration. Understanding why specific neuronal populations fail while others survive is essential for designing targeted therapies.

Can iPSC-based models reliably replicate protein quality control defects? Human iPSC-derived neurons offer the possibility of studying disease mechanisms in cells genetically identical to patients’ own neurons. The group develops and validates these models to bridge the gap between simpler experimental systems and clinically relevant human biology.

Inside the lab

The group combines molecular and cell biological approaches with a growing emphasis on human disease models.

iPSC reprogramming and differentiation. The lab generates iPSC lines from patient-derived cells and differentiates them into neuronal subtypes relevant to specific diseases. This platform—developed with expertise from the Horizon Europe SAME-NeuroID project and collaboration with the Paris Brain Institute (ICM) and Erasmus University Medical Center—is central to the group’s disease modeling work.

Protein quality control assays. The team uses biochemical and imaging-based approaches to measure the activity of specific PQC components—phosphatases, kinases, chaperones—in cellular disease models. These assays allow identification of molecular perturbations that precede or accompany neurodegeneration.

CRISPR-based gene editing. Isogenic cell lines—pairs of cells differing only in the specific genetic change under study—allow the group to attribute phenotypic differences directly to molecular causes rather than genetic background.

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Screening for PQC modulators. Building on the PPP1R15B inhibitor discovery, the group uses cell-based screens to identify compounds that can modulate protein quality control pathways in neurons. Hits are characterized for mechanism of action and validated in relevant disease models.

Collaboration within P4Health. The group collaborates with P4Health’s Bioanalytics Platform (P3) for proteomics and metabolomics readouts, and with the Functional Validation in Disease Models Platform (P4) for in vivo validation of candidates identified in cellular systems.