Construction is in full swing: neurons are stretching out their processes the way bricklayers stack up walls. But an error has crept into the blueprints. The protein tau, which normally serves as scaffolding for the cell's framework, starts dictating the wrong dimensions once it takes on its mutant form. In the brain of Drosophila, where human tau carrying the P301L mutation is switched on from birth, the building comes out crooked long before any tenants move in.
Tauopathies used to be seen as diseases of the mature brain: the protein piles up, neurons die, dementia sets in. But a new study in Drosophila shows that mutant tau P301L strikes the developing brain separately from its role in degeneration. In flies expressing this protein from the moment they hatch, the axons of Kenyon cells fail to form the normal lobes of the mushroom bodies, the centers of learning and memory. When expression was switched on only in adulthood, no defect appeared. So the protein wrecks the construction phase itself.
There is good news, though: the construction defect can be fixed. The researchers blocked the serotonin receptor 5-HT7, a molecular foreman's whistle that relays signals inside the cell. Genetic or pharmacological suppression of this receptor rescued the flies from behavioral and structural defects and also reduced the buildup of pathological forms of tau. Flies with the mutant protein that received the blockade lived longer, slept better, and climbed upward almost like healthy ones.
The mushroom bodies of Drosophila are named for their resemblance to a mushroom cap. They consist of just a few thousand neurons, yet they govern complex behavior, including learning and memory. In flies with mutant tau, these structures can be missing entirely, even though the neurons themselves stay alive.
The idea that neurodegeneration begins long before symptoms echoes Daniel Keyes's novel Flowers for Algernon, where the protagonist's intellectual decline is portrayed as the gradual unraveling of neural connections that were once formed.
Not published on arXiv. Here are its page, the PDF and the formalization: you can check it yourself, not only read our account.