Ezrin-mediated cell clearance: A new therapeutic target for adRP

Intartaglia, Daniela (2023). Ezrin-mediated cell clearance: A new therapeutic target for adRP. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.00016fb2

Abstract

Retinitis Pigmentosa (RP) is a genetic neurodegenerative disorder that causes photoreceptors cell death. Mutations in the Rhodopsin gene are common causes of autosomal dominant retinitis pigmentosa (adRP)and there is currently no available cure. Recent advances have pointed out the role of autophagy therapeutic modulation for treating genetic disorders characterized by mistrafficking and accumulation of mutated and unfolded proteins. In this regard, I recently identified Ezrin as an autophagic inhibitor in the retina. The goal of my thesis is to shed light on the mechanisms regulating cell clearance function in the RPE/retina crosstalk and to translate these discoveries into novel therapeutic strategies for adRP. I focused my effort in demonstrating the effect of Ezrin’s inhibition on clearance of misfolded RHOP23H aggregates, in vitro and in vivo. I demonstrated that pharmacological inhibition of Ezrin (NSC668394) promotes an increase of lysosomal degradation of disease-linked RHOP23H aggregates in vitro. Moreover, I demonstrated that therapeutic inhibition of Ezrin is able to decrease ER stress and to recover retina function in RHOP23H knock-in (RHOP23H/+) mice. Remarkably, treatment of RHOP23H/+ mice with NSC668394 resulted in a marked preservation of photoreceptor cells, robust decrease of cell death, culminating in an amelioration of the visual function. Finally, I gained insights into how Ezrin controls autophagy pathway and allow cellular clearance. In particular, I demonstrated that Ezrin coordinates and integrates the signal transduction pathways orchestrated by AKT/TSC with mTOR pathway to control autophagy. These findings open a new therapeutic perspective in which repression of the Ezrin may promote cell clearance reducing pathological accumulation of unfolded rhodopsin protein and rescues photoreceptor degeneration in several adRP models.

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