PRMT3-Mediated H4R3me2a Promotes Primary Age-Related Tauopathy by Driving Tau Hyperphosphorylation in Neuron

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Primary Age-Related Tauopathy (PART) and Alzheimer's Disease (AD) share tau pathology in the hippocampal-entorhinal system.
• PART exhibits greater tau hyperphosphorylation in the entorhinal cortex (EC) than AD, with underlying mechanisms unclear.
• Understanding Aβ-independent tau hyperphosphorylation is crucial for developing targeted PART therapies.

Purpose of the Study:

• To identify molecular drivers of tau hyperphosphorylation in PART.
• To elucidate the mechanistic pathway of Aβ-independent tau hyperphosphorylation.
• To evaluate PRMT3 inhibition as a therapeutic strategy for tauopathies.

Main Methods:

• Transcriptomic profiling of postmortem EC tissues.
• In vitro and in vivo functional validation of identified targets.
• Assessment of a selective PRMT3 inhibitor (SGC707) in reducing tau hyperphosphorylation.

Main Results:

• Protein Arginine Methyltransferase 3 (PRMT3) was identified as a critical driver of tau hyperphosphorylation.
• PRMT3 upregulates miR-448 via H4R3me2a, which suppresses IGF1R, activating GSK3β and promoting tau hyperphosphorylation.
• SGC707 treatment significantly reduced tau hyperphosphorylation in experimental models.

Conclusions:

• The PRMT3/H4R3me2a/miR-448 axis is a key regulatory pathway in PART tau hyperphosphorylation.
• PRMT3 inhibition presents a promising therapeutic avenue for PART and other tauopathies.
• Targeting PRMT3 offers a novel strategy for managing neurodegenerative tauopathies.