Faulty tau protein disrupts transport inside neurons
In Alzheimer’s disease, the tau protein accumulates in neurons in an abnormal form. A new study shows how that change disrupts the internal transport network of nerve cells, a system that is critical for neuronal survival.
Tau is a protein that normally supports the internal structure of neurons. It binds to microtubules, the tiny tubes that run through the cell like an internal skeleton. Nutrients, waste products and organelles are all transported along those tubes. In Alzheimer’s and other tauopathies, tau becomes hyperphosphorylated, meaning that an abnormally high number of phosphate groups are attached to the protein. That changes how tau behaves.
Tau normally forms a protective envelope
In healthy neurons, tau binds cooperatively with other tau molecules to form a continuous envelope around the microtubules. That envelope controls which transport proteins can move along the tubes and which cannot. Hyperphosphorylated tau no longer does this: it fails to form an envelope, is distributed more loosely along the neuron and detaches from microtubules more rapidly.
This has concrete consequences for transport. The researchers, who published their findings in eLife, studied two types of transport proteins: KIF5C and KIF1A. Normally, tau strongly inhibits KIF1A. With hyperphosphorylated tau, that inhibition worsens, disrupting the movement of lysosomes, the waste-processing structures of the cell. Lysosomal transport is essential for clearing damaged cellular material.
An early problem in cellular waste disposal
The disrupted lysosomal transport may be an early sign of neurodegeneration, occurring before the neuronal damage visible in later stages of Alzheimer’s. The researchers found that mice in which tau had been knocked out showed a similar pattern to mice with hyperphosphorylated tau: in both cases, lysosomes moved too fast and in an uncontrolled manner. This suggests that tau acts as a regulatory brake, and that both too little and the wrong form of tau cause problems.
The study does not clarify how these findings translate to clinical treatments for Alzheimer’s patients. But it gives researchers a clearer picture of how tau abnormalities cause neuronal damage well before nerve cells die.
Want to research this yourself?
Search for example:
- tau hyperphosphorylation microtubule transport
- lysosomal dysfunction tauopathy
- KIF1A motor protein neurodegeneration