Tubulin redirects Alzheimer's and Parkinson's proteins away from toxic clumping

Think of Tau and alpha-synuclein as proteins with dual careers. In healthy neurons, they help build and stabilize microtubules -- the internal scaffolding and transport network that keeps nerve cells functional. In Alzheimer's and Parkinson's disease, these same proteins misfold, clump together into toxic aggregates, and destroy the neurons they once supported. The question researchers have struggled with is how to stop the harmful career path without disrupting the helpful one.

A team at Baylor College of Medicine, publishing in Nature Communications, now proposes an answer that does not involve blocking or eliminating either protein. Instead, they found that tubulin -- the building block of the microtubules themselves -- can redirect Tau and alpha-synuclein away from aggregation and toward their normal, constructive roles.

The droplet problem

Both Tau and alpha-synuclein carry out their functions inside tiny liquid droplets called condensates that form within neurons. These droplets concentrate the proteins and facilitate their interactions. The trouble is that the same condensates also provide the environment where misfolding and toxic aggregation can begin. Block the droplets entirely, and you lose the healthy functions. Leave them alone, and disease-associated aggregation proceeds unchecked.

"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 Allan Ferreon, associate professor of biochemistry and molecular pharmacology and co-corresponding author of the study.

Giving the troublemakers something productive to do

First author Lathan Lucas put it more plainly: "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. We found that tubulin can drive Tau and alpha synuclein troublemakers down a healthy path."

Using biochemical and biophysical techniques, high-resolution microscopy, and neuronal-based assays, the team demonstrated that when tubulin levels are adequate, Tau and alpha-synuclein within condensates shift away from forming toxic aggregates and instead promote the assembly of healthy microtubules. The proteins still concentrate in droplets. They still interact with each other. But the presence of tubulin changes what they do inside those droplets.

Conversely, when tubulin levels are low -- as has been documented in Alzheimer's disease -- microtubules are less abundant, and the proteins default to their aggregation-prone behavior. The team's data suggest that tubulin availability may function as a kind of molecular switch, tipping the balance between healthy microtubule assembly and pathological clumping.

Reframing tubulin's role in neurodegeneration

"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."

This reframing is noteworthy because most therapeutic approaches to neurodegenerative protein aggregation focus on either preventing the proteins from interacting (which risks disrupting normal function) or clearing the aggregates after they form (which has proven difficult in clinical trials). A strategy that keeps the proteins active but redirects their behavior is conceptually different from either approach.

Laboratory findings, clinical distance

The experiments were conducted using purified proteins, cellular assays, and neuronal models -- not in living animals with neurodegenerative disease. Whether boosting tubulin levels in an aging human brain is feasible, safe, and sufficient to prevent or reverse aggregation remains entirely undemonstrated. Tubulin is not a drug; it is a structural protein that the body produces on its own, and artificially increasing its concentration in specific brain regions presents delivery challenges that the current study does not address.

The work also focused on Tau and alpha-synuclein in isolation and in combination. In actual Alzheimer's and Parkinson's disease, the biochemical environment is far more complex, involving inflammation, oxidative stress, impaired protein clearance systems, and genetic factors that vary from patient to patient.

Still, the finding that tubulin can competitively redirect these proteins within their native condensate environment opens a new angle on therapeutic strategy -- one that works with the biology rather than against it.

The study was supported by NINDS-NIH grant R01 NS105874, Welch Foundation grant Q-2097-20220331, and NIGMS-NIH grant R01 GM122763. Additional contributors include co-first author Phoebe S. Tsoi, My Diem Quan, Kyoung-Jae Choi, and co-corresponding author Josephine C. Ferreon.