 Previously overlooked, these tyrosine amino acid residues of the protein tau could play a pivotal role in regulating the functions of this protein in health and disease. Targeting these residues could lead to new forms of therapy that modify the progression of brain disorders. The protein tau is implicated in the development of several neurodegenerative disorders including Alzheimer's, PIX, and Parkinson's disease. Normally, tau acts as a stabilizing scaffold for the microtubules that make up the cellular skeleton and help with cell division. But in the brains of people with Alzheimer's, tau proteins become detached and aggregate into the wiring tangles that have become a hallmark of the disease. For that reason, scientists have dedicated much research to the part of tau responsible for clinging on to microtubules. Something suggest that this region known as the microtubule binding domain could be linked to the subsequent aggregation of tau. At the very core of this region is residue tyrosine 310, which together with four other tyrosines along tau holds the key to potentially preventing tau aggregation. Interestingly, however, few studies have explored its role in tau pathologies. To address this gap, researchers from the Lashwell Laboratory at EPFL's BrainMind Institute in Switzerland examined what happens when these tyrosines are altered by a post-translational modification known as protein phosphorylation. Through a combination of highly precise mutation and enzyme manipulation, the team decorated each site with phospho groups in five distinct patterns. Phosphorylation at all five tyrosine sites? At all sites except tyrosine 310 or 394, and at only one site, tyrosine 310 or 394. Results showed that phosphorylation at tyrosine 310 but not at tyrosine 394 was sufficient to inhibit the fibrillation of tau. When the other tyrosine residues in the N-terminal domain were also phosphorylated, the inhibitory effect was observed. These findings were confirmed when the investigators looked at the microtubule binding domain only. There again, phosphorylation at tyrosine 310 alone was sufficient to attenuate the fibrillation of this highly aggregation-prone domain of tau. It also regulates tau binding to microtubules and membranes. Notably, at tyrosine 310, phosphorylation led to local structure modifications in the microtubule binding domain. These changes reduced the region's ability to adopt the beta-sheet conformation that makes tangle formation easier. These findings support previous studies from the Lashwell group demonstrating that phosphorylation and hyperphosphorylation of tau, in this case at tyrosine residues, inhibits rather than promotes tau aggregation. Collectively, these findings call for revisiting the widely held view that hyperphosphorylation drives pathology formation in Alzheimer's disease and other tauopathies, and they point toward phosphorylation as a target for the development of desperately needed therapeutic strategies for Alzheimer's and tauopathies.