2025
Molecular Therapy

The impact of tau deletion on Huntington’s disease: An in vivo perspective

Authors:

Eva Lepinay, Martine Saint-Pierre, Maxime Teixeira, Marta Snapyan, Abid Oueslati, Martin Parent, Melanie Alpaugh, Francesca Cicchetti

Keywords:

zQ175; tau knockout mice; behavior; mutant huntingtin; microtubule-associated proteins; tubulin

Abstract:

Although an emerging body of evidence suggests that abnormal forms of tau are present and contribute to Huntington’s disease (HD)—a genetic neurodegenerative disorder primarily characterized by the aggregation of the mutant huntingtin (mHtt) protein affecting cognitive, motor, and psychiatric function—it is not clear to what extent this is relevant to the disease phenotype, and hence future treatments. We therefore generated a novel murine model by crossing heterozygous zQ175 knockin HD mice with homozygous tau knockout mice (mTKO). Tau deletion exacerbated both motor and cognitive deficits in zQ175/mTKO mice, which was accompanied by increased mHtt aggregation and alterations in microtubule dynamics, including dysregulated expression of microtubule-associated proteins, aberrant perinuclear β-tubulin accumulation, and microtubule destabilization. Combined, our findings unveil a previously unrecognized protective role of non-hyperphosphorylated tau in maintaining cytoskeletal homeostasis in HD and highlight a functional overlap between tau and huntingtin in regulating aggregate dynamics and cytoskeletal integrity. Our findings complement previous reports suggesting that reducing tau levels could mitigate disease pathology in HD mouse models.