Pharmacological Therapeutic Interventions in Anatomical Aging and Molecular Imaging for STUB1 Ataxias (2024)

Undergraduate: Joe Danica Inigo

Faculty Advisor: Jonathan Schisler
Department: Pharmacology -- McAllister Heart Institute

---

Necroptosis is a programmed cell death pathway found in cells, and one way it is regulated is through the carboxyl terminus of heat shock 70-interacting protein (CHIP). Mutations in CHIP can result in increased necroptotic activity as demonstrated in mouse models with ablated CHIP function. Thus, manipulations can change the necroptotic activity within the brain, providing the potential to serve as a therapeutic intervention for neurodegenerative diseases like STUB1 ataxias which are caused by CHIP polymorphisms. Administration of the drug Necrostatin-2 racemate (Nec-1s) influences the expression of proteins that interact with CHIP, thus reducing necroptotic activity. Mice received either saline or Nec-1s throughout the study period. Anatomical aging was analyzed through DEXA scans, yielding information regarding the skeletal composition of the mice. At the end of the study, brain slices were immunostained to reveal information on the structural integrity and cell makeup of the brain slices. QuPath analyses were performed on these slides to acquire quantitative values of neuronal cell counts. While definitive associations cannot yet be made due to the incomplete acquisition of data and results, there does appear to be a trend with pharmacological administration and anatomical aging and molecular imaging data. Mice given Nec-1s appear to have less neurodegeneration compared to mice given the control, saline, as seen with decreased growth and increased neuronal cell count, particularly Purkinje cell count. Completion of data acquisition and analysis will provide more definitive information on the associations between our study variables.