Study Identifies New Biological Pathways for Neurodegenerative Treatments

Researchers estimate that nearly 50 percent of people will someday be affected by dementia, either as patients or caregivers. HHMI Investigator Roy Parker notes that even this statistic may understate its true impact.

Alzheimer's and other neurodegenerative diseases are very expensive financially, but also carry an enormous emotional burden," he says. "And as our population lives longer, more of us will be affected."

Roy Parker, Howard Hughes Medical Institute  

Motivated by the magnitude of the problem, Parker redirected his lab at the University of Colorado, opens in a new tab from its decades-long focus on RNA decay toward neurodegenerative disease. "Because HHMI funds people, not projects, I was able to pursue my interests - even as they evolved," explains Parker.

He began studying the mechanisms underlying neurodegenerative diseases to identify where his expertise could have the greatest impact. That search led him to a protein called tau. 

The Chain Reaction Behind Neurodegeneration 

Neurodegenerative diseases such as Alzheimer's, Parkinson's, and ALS share a common underlying feature: misfolded proteins. The aberrant structure - the misfolded protein, which Parker calls a seed - can enter into normal cells and "infect" them with the same misfold, causing spread across the brain.

When proteins lose their proper shape, they are unable to carry out their normal roles. Worse still, they can accumulate into toxic aggregates inside cells. Although different proteins are involved in each disease, the outcome is similar: misfolded protein aggregates contribute to neuron damage and death. Because the brain has little ability to replace lost neurons, this gradual loss leads to a steady decline in memory, movement, and other essential functions. 

Tracking Toxic Tau Through the Cell 

One particularly insidious misfolded protein is tau, which according to Parker, is involved in about 80 percent of neurodegenerative diseases, including Alzheimer's. As a longtime RNA researcher, Parker was particularly intrigued by tau, which - when functioning properly - can serve as a good RNA-binding protein. He decided to dig into the mechanism of how misfolded tau grows and spreads, hoping to find opportunities to interrupt the vicious cycle.

Using high-resolution microscopes, Parker's team captured real-time images of misfolded tau protein seeds entering cells. They noticed that tau seeds often join an assembly of RNA-binding proteins, including a large protein called SRRM2 that normally plays an important role in RNA processing. Then, normal tau proteins also joined the seed to form larger tau clumps, driving the acceleration of additional damage to the cell.

The presence of SRRM2 alongside tau clumps in post-mortem Alzheimer's brain tissue suggests this process also occurs in people and may contribute to disease progression.

A New Strategy to Target Tau

Now that he knew where in the cell these tau aggregates form, Parker set out to identify other cellular components that might contribute to disease - or be harnessed to counter it. His team discovered that polyserine, a short stretch of amino acids in the SRRM2 protein, tends to bind tightly to tau aggregates and can worsen their effects.

But Parker also recognized an opportunity to turn this interaction to their advantage. He used polyserine as an address tag, guiding helpful proteins to the tau aggregates. 

Specifically, his team recruited FAF2, a naturally occurring protein that engages in protein quality control. The polyserine delivered FAF2 directly to the tau aggregates, where it helped to reduce toxic tau growth, protect neurons, and even improve brain function in mouse models. If the pathology of the tau problem comes from within the cell, so too does Parker's solution: redirecting the cell's own machinery to target and disable tau.

Parker's work is guided by a single goal: to uncover findings that can, someday, translate into neurodegenerative disease therapies for people. One idea he would like to see explored is a drug that could bind the two proteins together, linking the restorative protein FAF2 directly to tau aggregates.

He is also mindful of the broader challenge: Given the scale of neurodegenerative disease, any effective treatment must also be accessible and affordable. "About 30 percent of people living in this country take a statin for heart disease," he says. "Can you imagine if we had a kind of statin for neurodegenerative disease?"