In a study published in Nature Communications, the researchers found that tubulin, a protein that serves as the building block of microtubules, may help prevent these toxic accumulations. Microtubules act as the cell's internal 'railway tracks,' helping transport materials and maintain structure. According to the findings, tubulin can keep Tau and alpha synuclein from forming damaging aggregates and instead encourage them to perform their normal functions inside healthy neurons.

Toxic Protein Clumps and Brain Disease

"Tau and alpha synuclein are well known for their roles in neurodegenerative diseases like Alzheimer's and Parkinson's. In these conditions, these proteins can misfold, stick together and form harmful aggregates that damage neurons and contribute to memory loss, movement problems and other symptoms," said first author Dr. Lathan Lucas, postdoctoral associate of biochemistry and molecular pharmacology in Dr. Allan Ferreon's lab.

"But Tau and alpha synuclein also fulfill essential functions in healthy neurons - they help maintain cell structure and support communication by interacting with tubulin and contributing to microtubule assembly and stabilization."

Tau and alpha synuclein carry out both their beneficial and harmful activities within tiny cellular droplets known as condensates. Because these droplets are involved in disease-related processes, scientists have considered preventing their formation as a possible treatment strategy. However, condensates also play important roles in normal brain function, raising concerns that eliminating them could disrupt healthy neuronal activity.

Redirecting Proteins Toward a Healthy Role

"This led us to the following idea: what if instead of preventing the formation of droplets, we created conditions that would drive Tau and alpha synuclein inside the droplets toward their healthy path, discouraging them from taking the disease path?" said Ferreon, associate professor of biochemistry and molecular pharmacology and co-corresponding author of the work.

Lucas offered an analogy to explain the concept.

"I think of Tau and alpha synuclein as troublemaker kids in school. You can keep them in the classroom with little to do but to act out or keep them engaged with schoolwork, sports or theater so they do not get in trouble," Lucas said. "We found that tubulin can drive Tau and alpha synuclein troublemakers down a healthy path."

To investigate the idea, the researchers combined biochemical and biophysical methods with high-resolution microscopy and neuron-based assays. Their goal was to determine whether tubulin could influence the behavior of Tau and alpha synuclein and prevent the formation of toxic aggregates within condensates.

Tubulin Acts as a Protective Factor

"When tubulin levels are low, as it has been found in Alzheimer's disease, microtubules are less abundant and Tau and alpha synuclein can form toxic aggregates," Lucas said.

"But when tubulin is present, Tau and alpha-synuclein shift away from harmful aggregates and instead promote the assembly of healthy microtubules," Lucas said. "Tubulin redirects the activity of these proteins by giving them something productive to do."

The findings suggest that tubulin may play a much more active role in protecting the brain than previously recognized.

"Our findings significantly shift tubulin's role in neurodegeneration, from a passive casualty of disease to an active protector against toxic protein aggregation," Ferreon said. "Boosting the tubulin pool, rather than blocking droplet formation, can curb toxic aggregation while preserving the healthy roles of Tau and alpha synuclein, offering a potential selective therapeutic strategy."

Other contributors to the study include co-first author Phoebe S. Tsoi, My Diem Quan, Kyoung-Jae Choi and co-corresponding author Josephine C. Ferreon, all at Baylor College of Medicine.

The research was supported by NINDS-NIH grant R01 NS105874, Welch Foundation grant Q-2097-20220331 and NIGMS-NIH grant R01 GM122763.