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FMRP attenuates Tau pathology through the CDK5/p35 signaling pathway

Shanshan Zhao1, Xiangyu Jiang1, Yiru Jiang1

  • 1Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China.

Neurobiology of Disease
|October 17, 2025
PubMed

Insights

Fragile X Messenger Ribonucleoprotein 1 (FMRP) levels decrease in tauopathy. Increasing FMRP reduces cognitive decline and Tau pathology by regulating p35 mRNA translation, offering a new therapeutic target for tauopathies.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Tauopathies are neurodegenerative diseases defined by Tau protein hyperphosphorylation and aggregation.
  • Fragile X Messenger Ribonucleoprotein 1 (FMRP) regulates mRNA translation and is implicated in neurodegenerative conditions.
  • The precise role of FMRP in tauopathy pathogenesis is not well understood.

Purpose of the Study:

  • To investigate the role of FMRP in tauopathy.
  • To elucidate the molecular mechanisms linking FMRP to Tau pathology.
  • To explore FMRP as a potential therapeutic target for tauopathy.

Main Methods:

  • Analysis of FMRP levels in hippocampus of tauopathy mouse models.
  • Overexpression of FMRP in the rTg4510 tauopathy mouse model.
  • Assessment of cognitive function, Tau hyperphosphorylation, and associated protein levels (CDK5, p35, p25).
  • RNA immunoprecipitation to identify FMRP targets.

Main Results:

  • FMRP levels were found to be decreased in the hippocampus of tauopathy mouse models.
  • FMRP overexpression ameliorated cognitive deficits and reduced Tau hyperphosphorylation.
  • FMRP overexpression decreased levels of CDK5, p35, and p25 proteins.
  • FMRP was identified to bind to p35 mRNA, suggesting translational regulation.

Conclusions:

  • FMRP plays a protective role in tauopathy by restraining Tau hyperphosphorylation.
  • FMRP regulates Tau pathology through binding and controlling p35 mRNA translation.
  • Targeting FMRP presents a novel therapeutic strategy for treating tauopathies.
Keywords:
Cyclin-dependent kinase 5Fragile X Messenger Ribonucleoprotein 1Tau hyperphosphorylationTauopathiesp25p35

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