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G272V and P301L Mutations Induce Isoform Specific Tau Mislocalization to Dendritic Spines and Synaptic Dysfunctions
Ke Yu1,2, Katherine R Yao1,3, Miguel A Aguinaga1,3
1Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455.
Summary
This study reveals distinct roles for 3R tau and 4R tau proteins in frontotemporal dementia (FTD). Different mutations cause tau isoforms to impair neuronal function through separate pathways, impacting excitatory synapses.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Tau pathologies are hallmarks of neurodegenerative diseases like Alzheimer's disease (AD), Lewy body dementia (LBD), chronic traumatic encephalopathy (CTE), and frontotemporal dementia (FTD).
- Tau protein exists in six isoforms, categorized as 3R tau or 4R tau based on microtubule-binding repeats, arising from alternative RNA splicing.
- While AD, LBD, and CTE feature both 3R and 4R tau, FTD predominantly involves 4R tau, with 3R tau implicated in Pick's disease.
Purpose of the Study:
- To investigate the specific roles of 3R tau and 4R tau isoforms in the pathogenesis of frontotemporal dementia (FTD).
- To elucidate the distinct molecular mechanisms by which different tau mutations affect neuronal function and synaptic integrity.
Main Methods:
- Utilized primary hippocampal cultures from neonatal rats to examine the effects of specific tau mutations (P301L for 4R tau, G272V for 3R tau).
- Assessed tau protein mislocalization to dendritic spines using microscopy.
- Measured changes in dendritic spine density and miniature excitatory postsynaptic currents (mEPSCs) to evaluate synaptic function.
Main Results:
- The P301L mutation (4R tau FTD) caused tau mislocalization to dendritic spines, affecting excitatory synaptic function independently of dynamin.
- The G272V mutation (Pick's disease/3R tau FTD) induced phosphorylation-dependent mislocalization of 3R tau, reducing spine density and mEPSC amplitude via a dynamin-dependent pathway.
- Overexpression of G272V 3R tau, but not 4R tau, led to reduced dendritic spine density and suppressed mEPSCs.
Conclusions:
- 3R tau and 4R tau isoforms play distinct roles in FTD pathogenesis, activating different signaling pathways to cause excitatory synaptic dysfunction.
- These findings highlight diverse mechanisms underlying tauopathies, including FTD, AD, LBD, and CTE, offering insights into isoform-specific therapeutic strategies.
