Lu, Bingwei

Loss of fragile X messenger ribonucleoprotein (FMRP) causes fragile X syndrome (FXS), an inherited neurodevelopmental disorder resulting in intellectual disability and autism spectrum disorder; however, the molecular function of FMRP remains uncertain. Here, using cell lines and fibroblasts and induced pluripotent stem cell–derived neurons from healthy individuals and patients with FXS, we showed that FMRP regulates collided ribosomes by recruiting activating signal cointegrator 1 complex subunit 3 (ASCC3), an early-acting ribosome-associated quality control (RQC) factor to collided ribosomes, and either positively or negatively regulating translation, depending on transcript context. Disease-associated ASCC3 variants that perturbed ASCC3-FMRP interaction were also found to be defective in ribosome association and handling of collided ribosomes. In cells of a patient with FXS and the Fmr1 KO mouse model, ASCC3 abundance was reduced, and overexpression of ASCC3 in the brains of fetal Fmr1 KO mice promoted neuronal migration. In addition, CRISPR-mediated activation of ASCC3 by lateral ventricular injection of adeno-associated virus (AAV) ameliorated synaptic defects and improved locomotor activity, cognitive deficits, obsessive-compulsive–like behavior, and social interaction deficits after 1 month in 2-month-old Fmr1 KO mice compared with untreated Fmr1 KO controls. In conclusion, these data implicated FMRP in the handling of collided ribosomes to maintain protein homeostasis during neurodevelopment and synaptogenesis and demonstrated proof of concept that targeting RQC may offer alternative treatment strategies for FXS.

ABSTRACT Neurofibrillary tangles (NFTs) are a characteristic neuropathological feature of Alzheimer's disease (AD), and molecular chaperones appear to be involved in the removal of disease‐associated hyperphosphorylated tau, a primary component of NFTs. Here, novel HSP90 inhibitors were used to examine the impact of chaperone elevation on clearance of different tau species in transfected cells using a unique quantitative assay. The HSP90 inhibitors reduced levels of tau phosphorylated at proline‐directed Ser/Thr sites (pS202/T205, pS396/S404) and conformationally altered (MC‐1) tau species, an epitope that is immeasurable by standard Western blot techniques. The selective clearance of these phospho‐tau species and MC‐1 tau was mediated via the proteasome, while lysosomal‐mediated tau degradation seems to lack specificity for certain tau species, suggesting a more general role in total tau removal. Interestingly, tau phosphorylated at S262/S356 within the tau microtubule binding domain was minimally affected by chaperone induction. Overall, our data show that chaperone induction results in the selective clearance of specific phospho‐tau and conformationally altered tau species mediated by the proteasome; however, the apparent stability of pS262/S356 tau may also explain why MARK is able to regulate normal tau function yet still be linked to the initiation of pathogenic tau hyperphosphorylation in AD.