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CONVERGENT DYSREGULATION OF THE UBIQUITIN PROTEASOME SYSTEM IN <EM>FMR1</EM><SUP>-/Y</SUP> RATS
Scott Murray Corsand 2 co-authors
University of Edinburgh
FENS Forum 2026 (2026)
Barcelona, Spain
Board PS06-09PM-103
Presentation
Date TBA
Board: PS06-09PM-103
Event Information
Poster Board
PS06-09PM-103
Poster
View posterAbstract
In the developing and adult brain, synapses undergo constant remodeling—regulated by a complex interplay between local protein synthesis and degradation. In Fragile X Syndrome (FXS), protein synthesis and degradation rates are elevated, leading to a pathological shift in the synaptic proteome that causes synaptic dysfunction. Inhibiting protein synthesis reliably corrects FXS-associated phenotypes in preclinical models, but drugs targeting upstream regulators of protein synthesis have largely failed in clinical trials—prompting investigations into alternative treatment targets. Recently, we found that inhibiting the proteasome using bortezomib (BTZ) corrects protein synthesis rates and seizures in Fmr1 KO mice. However, it remains unknown which targets are corrected by BTZ and also if UPS function is affected in other FXS models. Here, we combined biochemical and proteomics from tandem ubiquitin binding entity (TUBE) pull downs from Fmr1 KO rat hippocampal slices and found convergent changes in UPS function. Future experiments will reveal if normalizing degradation rates of these conserved targets is sufficient to correct FXS-associated pathophysiology.
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