Impaired tau-microtubule interactions are prevalent among pathogenic tau variants arising from missense mutations

Area of Science:

• Neuroscience
• Cell Biology
• Genetics

Background:

• Tau is a microtubule-associated protein crucial for neuronal function.
• Aberrant tau aggregation forms pathological inclusions in tauopathies, including Alzheimer's disease.
• Missense mutations in the MAPT gene can cause frontotemporal dementias.

Purpose of the Study:

• To investigate the aggregation propensity and microtubule binding properties of additional tau mutants.
• To determine the common cellular dysfunctions caused by MAPT mutations.
• To explore potential therapeutic strategies for tauopathies.

Main Methods:

• Utilized a cell-based inclusion seeding assay to assess tau aggregation.
• Employed mammalian cell-based assays to evaluate tau's microtubule binding.
• Analyzed various tau mutants resulting from missense mutations.

Main Results:

• A limited number of tau variants showed modest in vivo aggregation propensity.
• Most tau mutants did not aggregate in the studied cell-based assays.
• Reduced microtubule binding was the most frequent dysfunction observed in tau variants.

Conclusions:

• Missense mutations in MAPT primarily impair tau's microtubule binding rather than causing aggregation.
• Microtubule-targeting therapies represent a potential treatment avenue for tauopathies.
• Understanding tau dysfunction is key to developing effective therapeutic interventions.