Excessive proteostasis contributes to pathology in fragile X syndrome

• Published in: Neuron (Cambridge, Mass.) Vol. 111; no. 4; pp. 508 - 525.e7
• Main Authors: Louros, Susana R., Seo, Sang S., Maio, Beatriz, Martinez-Gonzalez, Cristina, Gonzalez-Lozano, Miguel A., Muscas, Melania, Verity, Nick C., Wills, Jimi C., Li, Ka Wan, Nolan, Matthew F., Osterweil, Emily K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.02.2023
• Subjects: AGS; Animals; bortezomib; Bortezomib - metabolism; Bortezomib - therapeutic use; Disease Models, Animal; FMR1; fragile X; Fragile X Mental Retardation Protein - genetics; Fragile X Syndrome; inferior colliculus; Mice; Mice, Knockout; proteasome; Proteasome Endopeptidase Complex - metabolism; Proteasome Endopeptidase Complex - therapeutic use; Proteostasis; PSMB5; seizures; UPS; proteasome; PSMB5; FMR1; UPS; inferior colliculus; seizures; fragile X; proteostasis; bortezomib; AGS
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2022.11.012

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. [Display omitted] •Elevated UPS activity drives excessive protein degradation in Fmr1−/y synapses•Excessive protein synthesis and degradation are coupled in Fmr1−/y neurons•Normalizing UPS activity corrects hyperexcitability in Fmr1−/y inferior colliculus•Pharmacological or genetic UPS reduction prevents audiogenic seizures in Fmr1−/y mice Over-synthesis of proteins in neurons is a core problem in fragile X syndrome, the leading identified monogenic cause of autism. Here, the authors now show over-degradation of proteins is also a contributor to neuropathology. This indicates that the proteostasis cycle is elevated and that reducing protein degradation is a potential new therapeutic strategy.