Pathogenic MAPT mutations Q336H and Q336R have isoform-dependent differences in aggregation propensity and...

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Tauopathies, including Alzheimer's disease and frontotemporal dementia, involve tau protein aggregation in the brain.
• Microtubule-associated protein tau (MAPT) gene mutations cause familial frontotemporal dementia.
• Most studied tau mutations decrease microtubule binding, but Q336H and Q336R mutations are exceptions.

Purpose of the Study:

• To investigate the pathobiology of Q336H and Q336R MAPT mutations.
• To assess the aggregation propensity and microtubule binding of Q336H and Q336R tau mutants in different tau isoforms.
• To understand how these mutations affect microtubule dynamics and homeostasis.

Main Methods:

• Cell-based assays were used to evaluate tau mutants.
• Assessed aggregation propensity and microtubule binding affinity of Q336H and Q336R tau.
• Examined the interaction of mutant tau with different microtubule subpopulations (tyrosinated and acetylated).

Main Results:

• Q336R tau exhibited prion-like seeded aggregation.
• Both Q336H and Q336R tau mutants showed increased binding affinity to microtubules.
• Mutant tau isoforms differentially regulated tyrosinated and acetylated microtubule subpopulations.

Conclusions:

• Q336H and Q336R MAPT mutations may promote frontotemporal dementia through increased microtubule binding and hyperstabilization.
• This mechanism contrasts with other tau mutations that reduce microtubule binding.
• Pathogenic tau's interaction with microtubules is complex and isoform-dependent, impacting microtubule homeostasis.