Overlooked Tau-RNA Interaction May Play Key Role in Dementia

Summary: The interaction of Tau with RNA is a key stage in the development of Alzheimer’s disease and other dementias.

Source: University of Washington

Sometimes in science, “Eureka!” moments happen with surprisingly little effort. Sometimes they take years or decades to emerge. Such was the case with Brian Kraemer’s research team and their recent study of the protein tau and its impact on dementia diseases.

A paper, now available as a preprint from the journal Brain, identifies tau interactions with RNA, the nucleic acid that serves as the blueprint molecule for all our cellular machines, as a key stage in the development of Alzheimer’s disease and other dementia disorders.

The finding was reported by Kraemer and colleagues with the U.S. Department of Veterans Affairs and UW Medicine in Seattle.

The evidence, it turns out, had been hidden in plain sight in a research findings first published in the 1970s.

“This has given us pieces of the puzzle that we should have had years ago,” Kraemer said, “We have to pay more attention to tau.”

Tau, pronounced like “wow,” has a useful function. It plays the role of a bonding agent for microtubules that serve many key actions in cells. Scientists intently explored that role in early tau research, to great effect, especially in the area of chemotherapies.

“RNA is just a harder molecule to study and wasn’t nearly as trendy as microtubules,” Kraemer said. “Microtubules are involved in moving things around the cell. Tau is important for stabilizing microtubules and that’s how it was first discovered. But in the second paper that ever came out about tau, they noticed that it interacted with RNA. And then the field has mostly disregarded that observation for the past 45 years.”

When Kraemer’s lab began to study tau, the RNA interactions repeatedly showed up in their results. The constant presence of the nucleic acid involvement caused him to ask a simple question: Does tau prefer to bind with RNA or with microtubules? His lab then developed a test using monoclonal antibodies to compare tau’s affinity for each and found that, under lab conditions, tau prefers to bind with RNA.

Normally this is not a problem because tau doesn’t have opportunity to interact with RNA. But when it does, it creates neuropathological lesions leading to neurofibrillary tangles believed to be key contributors in most common types of dementia.

“It’s probably an early stage of the disease process: Tau comes off of microtubules and it gets onto RNA and that causes this disease process to begin to unfold,” Kraemer surmised. “In Alzheimer’s disease, RNA becomes partially uncoated and is further exposed to tau, and once that gets started, it becomes a self-reinforcing cycle of toxic aggregation.”

This shows tau-RNA
This antibody staining experiment shows tau-RNA complexes that have been dyed green. The tau-RNA complex staining strongly resembles neurofibrillary tangles, a hallmark of most kinds of dementia. Credit: Pamela J. McMillan

Neurodegenerative diseases involving tau include a long list of incurable maladies. In some, abnormal tau appears to be the primary cause. These are called pure tauopathies, and include frontotemporal lobar degeneration, progressive supranuclear palsy and Pick’s disease.

Alzheimer’s is called a mixed tauopathy because another protein, beta-amyloid, plays a role. Treatments for beta-amyloid, once thought promising, have been in recent headlines reporting mixed results from trials that found a drug doesn’t curb the disease, as hoped.

Kraemer thinks that means it’s time to turn to tau for long overdue answers.

“With beta-amyloid treatments for Alzheimer’s, we’re addressing half the disease, but not the other half,” he said.

“And if you’re only addressing one and not the other, that’s probably why treatment is not working very well. I don’t know that this is going to be a therapeutically tractable strategy, but it’s certainly an idea and one of those ideas is going to have to be successful for us to make progress on Alzheimer’s disease.”

About this genetics and Alzheimer’s disease research news

Author: Press Office
Source: University of Washington
Contact: Press Office – University of Washington
Image: The image is credited to Pamela J. McMillan

Original Research: Closed access.
Tau-RNA complexes inhibit microtubule polymerization and drive disease-relevant conformation change” by Pamela J McMillan et al. Brain


Tau-RNA complexes inhibit microtubule polymerization and drive disease-relevant conformation change

Alzheimer’s disease and related disorders feature neurofibrillary tangles and other neuropathological lesions composed of detergent-insoluble tau protein. In recent structural biology studies of tau proteinopathy, aggregated tau forms a distinct set of conformational variants specific to the different types of tauopathy disorders.

However, the constituents driving the formation of distinct pathological tau conformations on pathway to tau-mediated neurodegeneration remain unknown.

Previous work demonstrated RNA can serve as a driver of tau aggregation, and RNA associates with tau containing lesions, but tools for evaluating tau/RNA interactions remain limited.

Here we employ molecular interaction studies to measure the impact of tau/RNA binding on tau microtubule binding and aggregation. To investigate the importance of tau/RNA complexes (TRCs) in neurodegenerative disease, we raised a monoclonal antibody (mAb TRC35) against aggregated tau/RNA complexes.

Here we show native tau binds RNA with high affinity but low specificity, and tau binding to RNA competes with tau mediated microtubule assembly functions. Tau/RNA interaction in vitro promotes the formation of higher molecular weight tau/RNA complexes which represent an oligomeric tau species.

Co-expression of tau and poly(A)45 RNA transgenes in Caenorhabditis elegans exacerbates tau related phenotypes including neuronal dysfunction and pathological tau accumulation. TRC35 exhibits specificity for Alzheimer’s disease-derived detergent insoluble tau relative to soluble recombinant tau.

Immunostaining with TRC35 labels a wide variety of pathological tau lesions in animal models of tauopathy, which are reduced in mice lacking the RNA binding protein MSUT2. TRC-positive lesions are evident in many human tauopathies including Alzheimer’s disease, progressive supranuclear palsy, corticobasal degeneration, and Pick’s disease.

We also identify ocular pharyngeal muscular dystrophy as a novel tauopathy disorder where loss of function in the poly(A) RNA binding protein (PABPN1) causes accumulation of pathological tau in tissue from postmortem human brain. Tau/RNA binding drives tau conformational change and aggregation inhibiting tau mediated microtubule assembly.

Our findings implicate cellular tau/RNA interactions as modulators of both normal tau function and pathological tau toxicity in tauopathy disorders, and suggest feasibility for novel therapeutic approaches targeting TRCs.

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