Date of Award

2026

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Pharmacology and Experimental Therapeutics

First Advisor

Rocco Gogliotti

Abstract

Rett syndrome (RTT) is a severe neurodevelopmental disorder that is associated with loss-of-function mutations in the methyl-CPG binding protein 2 (MECP2) gene. There are limited therapeutic options to address the wide range of social, cognitive, motor, and respiratory symptoms that patients experience throughout their lifetime. To identify novel therapeutic targets, we leveraged a rare form of RTT known as MeCP2-mutation-negative or atypical RTT. Traditionally, RTT is first diagnosed clinically and then confirmed through the identification of mutations in the MECP2 gene. However, ~5% of RTT patients are found to be MeCP2-mutation-negative (atypical), despite sharing overlapping symptomology with typical RTT. We hypothesized that genes with conserved disruption in typical and atypical patient populations would be those most critical to their shared clinical presentation. Using a cohort of 40 autopsy samples from RTT patients, we identified five that were MeCP2-mutation-negative. We then conducted differential RNA sequencing on these samples relative to six typical RTT samples and nine neurotypical controls. These experiments revealed that pathways associated with heat shock factor 1 (HSF1) signaling are significantly elevated in both populations. To evaluate the impact of HSF1 on disease progression, we conducted experiments to pharmacologically activate and repress the heat shock response in mouse models of RTT. In these experiments, HSF1 inhibitors improved RTT-like phenotypes, while administration of activators resulted in convulsive behaviors and lethality, suggesting a pathogenic role. To understand this at the molecular level, we conducted in vivo hyperthermia experiments complemented with cellular stress array analyses. These results point to altered kinetics and magnitude of induction of cellular stress genes in the brain following thermal stress. In summary, our data show that increased expression of HS proteins is pathogenic in RTT, both at baseline and in response to stress, and that strategies to normalize the HS response have therapeutic potential.

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