FMRP attenuates Tau pathology through the CDK5/p35 signaling pathway

Tauopathies are a group of neurodegenerative disorders characterized by hyperphosphorylation and aggregation of the Tau protein. The Fragile X Messenger Ribonucleoprotein 1 (FMRP) is an RNA-binding protein known to regulate the translation of synaptic and signaling-related mRNAs. Recent evidence suggests its involvement in neurodegenerative diseases, including tauopathies. However, the underlying molecular mechanism remains unclear. In the present study, we found that the FMRP level was decreased in the hippocampus of tauopathy mouse models at pathological stages. Moreover, overexpression of FMRP significantly attenuated cognitive impairment and Tau hyperphosphorylation and reduced Cyclin-dependent kinase 5 (CDK5), p35, and p25 protein levels in the rTg4510 tauopathy model mice. Mechanistically, we found that FMRP bound to p35 mRNA. Together, our results identify a novel role of FMRP in restraining tau hyperphosphorylation through binding to the p35 transcript to regulate its translation, providing mechanistic insight into the therapeutic potential of targeting FMRP for tauopathy.