Molecular and Cellular Responses to Prion Strain Diversity: Single-Nucleus Transcriptomics and Laboratory Surveillance Approaches

Author

• Damian A. Gorski, The University of Texas MD Anderson Cancer CenterFollow

Author ORCID Identifier

0000-0001-6951-1456

Date of Graduation

8-2026

Document Type

Dissertation (PhD)

Program Affiliation

Neuroscience

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Claudio Soto

Committee Member

Fei Wang

Committee Member

Consuelo Walss-Bass

Committee Member

Juneyoung Lee

Committee Member

Zhongming Zhao

Abstract

Prion diseases are a group of irremediable and infectious neurodegenerative disorders caused by the misfolding and aggregation of the cellular prion protein PrPC, into a misfolded pathological form termed PrP^Sc. Despite decades of research, fundamental questions regarding the molecular mechanisms driving prion-induced neurodegeneration remain unresolved. Ongoing research efforts are complicated by the extraordinary resistance of PrPSc to conventional decontamination methods and its ability to adhere to surfaces while retaining infectivity. Recent occupational exposures underscore the significant biosafety challenges associated with prion research and highlight the urgent need for improved prion surveillance methods in both the laboratory and clinical setting.

This thesis addresses two interrelated dimensions of prion research. First, we detail the development and validation of a foam-swab surface sampling technique coupled with protein misfolding cyclic amplification (PMCA) for the detection of prion contamination on laboratory and other relevant surfaces. We demonstrate the capacity to detect prion strains most relevant to human health including Creutzfeldt-Jakob disease and bovine spongiform encephalopathy and conduct active prion surveillance in operational prion research facilities. Our findings demonstrate the utility of this technique for validating the completeness of decontamination methods and assessing the presence of prion accumulation on laboratory surfaces.

Second, we employ single nucleus RNA sequencing across two distinct murine prion strains and characterize the cell type-specific response across two brain regions. Our findings reveal a core strain independent transcriptomic response across key brain cell populations including astrocytes, microglia, and excitatory neurons. Furthermore, we identify synaptic membrane dysfunction as a hallmark of prion-induced neuronal degeneration and nominate candidate molecular determinants of prion neurodegeneration for future investigation.

Recommended Citation

Gorski, Damian A., "Molecular and Cellular Responses to Prion Strain Diversity: Single-Nucleus Transcriptomics and Laboratory Surveillance Approaches" (2026). Dissertations and Theses (Open Access). 1560.
https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1560

Keywords

prion, transcriptomics, strains, cellular response, laboratory safety