Tau excess impairs mitosis and kinesin-5 function, leading to aneuploidy and cell death

Area of Science:

• Cell Biology
• Neuroscience
• Genetics

Background:

• Cell cycle defects and aneuploidy are observed in neurodegenerative diseases, including Alzheimer's disease (AD).
• The role of the microtubule (MT)-binding protein Tau in these mitotic defects remains largely unknown.
• Excess Tau protein in the brain and cerebrospinal fluid is a hallmark of AD.

Purpose of the Study:

• To investigate the in vivo effect of excess human Tau (hTau) protein on cell mitosis.
• To elucidate the underlying mechanisms by which Tau affects cell division.
• To explore the implications of Tau-induced mitotic defects in neurodegenerative disease pathogenesis.

Main Methods:

• Utilized the Drosophila developing wing disc epithelium as a model system to study mitosis.
• Assessed the impact of excess hTau on spindle formation, cell cycle progression, and cell death.
• Investigated the role of the MT-binding domain of Tau and its interaction with kinesin motor proteins.

Main Results:

• Excess hTau induced mitotic arrest characterized by monopolar spindles in Drosophila.
• These mitotic defects resulted in aneuploidy and apoptotic cell death.
• The MT-binding domain of hTau was responsible for inhibiting the kinesin Klp61F (Eg5), a homolog of human KIF11, thereby disrupting mitosis.

Conclusions:

• Microtubule-bound Tau inhibits Eg5 kinesin function, leading to cell division defects and aneuploidy.
• These findings provide a novel mechanistic link between Tau pathology and mitotic dysfunction in neurodegenerative diseases.
• The study demonstrates conserved deleterious effects of Tau on mitosis across different cell types and species, including human HeLa cells.