Scientists at Baylor College of Medicine have identified a potential new approach to tackling Alzheimer’s and Parkinson’s diseases. Both conditions are associated with the accumulation of harmful clumps formed by the proteins tau and alpha-synuclein in the brain.
In a study published in nature communicationsResearchers have discovered that tubulin, a protein that functions as a component of microtubules, may help prevent the buildup of these toxic substances. Microtubules act as “railroads” inside cells, helping to transport materials and maintain structure. The findings show that tubulin can prevent tau and alpha-synuclein from forming damaging aggregates and instead encourage them to perform their normal functions in healthy neurons.
Toxic protein clumps and brain disease
“Tau and alpha-synuclein are well known for their role in neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. In these diseases, these proteins can misfold and stick together to form harmful aggregates, damaging neurons and causing memory loss, movement disorders, and other symptoms,” said first author Dr. Lathan Lucas, a postdoctoral fellow in biochemistry and molecular pharmacology in the lab of Dr. Alan Ferreon.
“However, tau and alpha-synuclein also perform essential functions in healthy neurons. They interact with tubulin and contribute to the assembly and stabilization of microtubules, thereby helping maintain cell structure and supporting communication.”
Tau and alpha-synuclein carry out both beneficial and harmful activities within small 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 an important role in normal brain function, raising concerns that removing them could interfere with healthy neural activity.
Redirect protein toward a healthy role
“This led us to think: What if, instead of preventing the droplets from forming, we created conditions that moved the tau and alpha-synuclein within the droplets in a healthy direction and stopped them from moving toward disease?” says Ferreon, associate professor of biochemistry and molecular pharmacology and co-corresponding author of the paper.
Mr. Lucas used an analogy to explain this concept.
“I think tau and alpha-synuclein are the kids who get into trouble at school. We can keep them in the classroom and do little and act out, or we can keep them busy with schoolwork, sports, and theater so they don’t get in trouble,” Lucas said. “We discovered that tubulin can steer tau and alpha-synuclein troublemakers in a healthy direction.”
To investigate this idea, the researchers combined biochemical and biophysical techniques with high-resolution microscopy and neuron-based assays. Their goal was to determine whether tubulin can influence the behavior of tau and alpha-synuclein and prevent the formation of toxic aggregates within condensates.
Tubulin functions as a protective factor
“Low tubulin levels, as seen in Alzheimer’s disease, can reduce the amount of microtubules and allow tau and alpha-synuclein to form toxic aggregates,” Professor Lucas said.
“However, in the presence of tubulin, tau and alpha-synuclein move away from harmful aggregates and instead promote healthy microtubule assembly,” Lucas says. “Tubulin redirects the activity of these proteins by giving them productive activity.”
The findings suggest that tubulin may play a much more active role in brain protection than previously appreciated.
“Our findings significantly shift the role of tubulin in neurodegeneration from passive disease-induced damage to an active protector against toxic protein aggregation,” said Professor Ferreon. “Rather than blocking droplet formation, enhancing the tubulin pool can suppress toxic aggregation while preserving the healthy role of tau and alpha-synuclein, offering the potential for a selective therapeutic strategy.”
Other contributors to the study include co-first authors Phoebe S. Tsoi, Mai Diem Quang and Kyung-Jae Choi, and co-corresponding author Josephine C. Fereon, all of Baylor College of Medicine.
This research was supported by NINDS-NIH grant R01 NS105874, Welch Foundation grant Q-2097-20220331, and NIGMS-NIH grant R01 GM122763.
