Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons

Tau, a crucial protein for neuronal microtubule organization and intracellular transport, plays a significant role in brain health. When the protein becomes hyperphosphorylated, it can lead to neurodegenerative diseases like Alzheimer's. Tau creates a protective barrier along microtubules, which helps regulate the activity of motor proteins and other microtubule-associated proteins (MAPs).

However, the exact consequences of tau hyperphosphorylation on its function are not fully understood. In this study, researchers examined tau phospho-variants both in vitro and in living neurons. They discovered that tau hyperphosphorylation impairs its ability to bind cooperatively with microtubules and interferes with lysosome transport.

When tau is hyperphosphorylated, it no longer forms protective envelopes, spreads more evenly along the axon, and detaches more quickly from microtubules. Although hyperphosphorylation weakens its inhibitory effect on KIF5C, it strongly inhibits KIF1A. The altered inhibition leads to reduced processivity but accelerates detachment of lysosomes.

Notably, while phospho-resistant tau continues to inhibit processive lysosome movement, hyperphosphorylated tau weakens its regulation of lysosome transport, similar to the effects seen in tau knockout neurons with enhanced processivity. In conclusion, these findings highlight how hyperphosphorylation disrupts tau's protective envelope and hampers lysosome transport, potentially contributing to early stages of degradative pathways that can lead to neurodegeneration.