Excessive proteostasis contributes to pathology in fragile X syndrome

Abstract

In fragile X syndrome (FX), the leading monogenic cause of autism, excessive neuronal protein synthesis is a core pathophysiology; however, an overall increase in protein expression is not observed. Here, we tested whether excessive protein synthesis drives a compensatory rise in protein degradation that is protective for FX mouse model (Fmr1^-/y) neurons. Surprisingly, although we find a significant increase in protein degradation through ubiquitin proteasome system (UPS), this contributes to pathological changes. Normalizing proteasome activity with bortezomib corrects excessive hippocampal protein synthesis and hyperactivation of neurons in the inferior colliculus (IC) in response to auditory stimulation. Moreover, systemic administration of bortezomib significantly reduces the incidence and severity of audiogenic seizures (AGS) in the Fmr1^-/y mouse, as does genetic reduction of proteasome, specifically in the IC. Together, these results identify excessive activation of the UPS pathway in Fmr1^-/y neurons as a contributor to multiple phenotypes that can be targeted for therapeutic intervention.

Keywords: AGS; FMR1; PSMB5; UPS; bortezomib; fragile X; inferior colliculus; proteasome; proteostasis; seizures.