Researchers Analyze Neurodegeneration at Single-Neuron Level

While the molecular and cellular mechanisms of neurodegenerative diseases have slowly been unfolding in recent years, much remains unknown. In a first-of-its-kind study, a team of researchers at EPFL identified how specific proteins, such as Tau, impact adult human brains at the single-neuron level. Their work, published in the journal Nature Communications, revealed surprising findings about how protein complexes can impact synaptic health.

“If we can stop or slow down the earliest disconnection of neurons, we may slow down the subsequent steps that happen as neurons start to degenerate,” says lead study author Brian McCabe, who is also the director of the Laboratory of Neural Genetics and Disease and a Professor at the EPFL School of Life Sciences.

The team began by engineering Drosophila flies to express the human protein Tau, which is known to be involved in neurodegenerative disorders such as Alzheimer’s and Parkinson’s. They found that, in addition to having a significantly shorter lifespan than controls, the flies expressing human Tau showed a substantial loss of synapses compared to controls.

“By the time the axon was retracted, the neurons were no longer part of a functional circuit,” McCabe says. “We need to intervene in these very early stages, because when neurons are dying, the battle is already lost.”

To further investigate their findings, the research team conducted further genetic and computational techniques to discover that the loss of protein complexes, called the retromer, accelerated neurodegeneration. This complex acts as a “recycling system” for proteins within the body and has been found to be mutated in people with Parkinson’s. By blocking the activity of the retromer complex, the researchers noted increased levels of a shortened form of Tau that exacerbates neurotoxicity.

McCabe and colleagues hypothesized that, when this retromer activity is reduced, Tau proteins aggregate inside the cell to be “trimmed” by specialized enzymes called caspases. Their findings suggest that dampening retromer activity slows down Tau activity, allowing caspases to cut Tau into the shorter form, thus damaging more neurons.

For future work, the team is investigating how specific drugs might enhance the Tau’s trafficking and potential reductions in neurotoxicity. Additionally, they speculate that the shortened version of Tau might act as an efficient biomarker for brains impacted by neurodegenerative diseases and that screening for atypical protein levels could be used as a proxy for drug efficacy.