Journal News

JBC: How do protein tangles get so long?

Laurel Oldach
June 01, 2019

Long before Alzheimer’s disease patients notice any symptoms, neurofibrillary tangles composed of tau protein filaments begin to form in their brain cells. How toxic these aggregates are and how well they spread depend on their size — that is, the number of tau monomers they contain. However, scientists studying tangle formation have not been able to explain why different sizes of tau aggregates appear in disease.

But now researchers have discovered that instead of adding just one protein at a time, fibrils of various lengths can join end-to-end to create one larger filament. The finding, published in the Journal of Biological Chemistry, helps explain how fibrils can grow to hundreds of nanometers. It also could help researchers understand mechanisms of an emerging group of drug candidates designed to inhibit tau aggregation.

A common simple model of tau aggregation and fibril formation includes two steps. First, two tau proteins bind slowly; additional tau molecules latch on quickly.

Carol Huseby, then a graduate student in Jeff Kuret’s lab at THE Ohio State University, worked with Ralf Bundschuh to expand this mathematical model to include other known ways that tau fibrils behave. Scientists have observed, for example, that sometimes one fibril fragments into two. Or a new fibril can nucleate in the middle of an existing fibril.

Tau proteins labeled with three fluorescent dyesTau proteins labeled with three fluorescent dyes were allowed to aggregate in separate test tubes, shown in the three images at left. The different colored fibrils were mixed in a fourth test tube, at right, resulting in long fibrils with short sections of each color. Carol Huseby/The Ohio State University
The simple model predicted many short fibrils. But Huseby knew that, under a microscope, aggregated tau appears as a smaller number of long fibrils. That discrepancy suggested that something was happening in the real world that hadn’t been accounted for in the model. They hypothesized that short fibrils could attach end-to-end to get longer.

To test the hypothesis, Huseby labeled tau proteins with three fluorescent colors and allowed them to aggregate in separate test tubes. Then she mixed the different colored fibrils in a fourth test tube.

Images taken with a super-resolution fluorescence microscope showed long fibrils with short sections of each color, indicating that fibrils from the original test tubes had joined ends to form longer fibrils. Control experiments established that this can’t be explained by labeled molecules’ preference for like labels.

After Huseby incorporated this new mechanism into the model, it produced a better description of what purified tau proteins were doing as they formed aggregates. This study is the first to show that the fibrils can elongate by more than a single tau protein at a time.

Alzheimer’s disease researchers still are trying to discern whether tau fibrils are a cause or simply an effect of the disease. Transmission of fibrils from one cell to another may contribute to the spread of disease in the brain. A very long fibril, according to Kuret, is unlikely to spread in this way. “But once it’s broken up into little pieces, those can diffuse,” he said, “facilitating their movement from cell to cell.”

This study used just one type of tau. Six isoforms are known, and phosphorylation and other changes increase the protein’s complexity. The researchers plan to incorporate these variables in future work and to use the model to understand how tau inhibitors change the protein aggregates’ behavior.

Laurel Oldach

Laurel Oldach is a science writer for the ASBMB.

Join the ASBMB Today mailing list

Sign up to get updates on articles, interviews and events.

Latest in Science

Science highlights or most popular articles

Gut microbiome shaped by dietary sphingolipids
Journal News

Gut microbiome shaped by dietary sphingolipids

September 22, 2020

A new tracing method described in the Journal of Lipid Research offers clues on how a macronutrient interacts with the microbes that live inside us.

From the journals: JBC
Journal News

From the journals: JBC

September 21, 2020

Proteases that fire up the flu. A sulfate pocket to take out MRSA. Proteins that prompt cancer protrusions. Read about recent papers on these topics and more.

AeroNabs promise powerful, inhalable protection against COVID-19
News

AeroNabs promise powerful, inhalable protection against COVID-19

September 20, 2020

As the world awaits vaccines to bring the COVID-19 pandemic under control, UC San Francisco scientists have devised a novel approach to halting the spread of SARS-CoV-2, the virus that causes the disease.

Keeping bone and muscle strong on the ISS
News

Keeping bone and muscle strong on the ISS

September 19, 2020

Researchers helped mice stay mighty with an experiment to counter the effects of microgravity. The gene treatment might also enhance muscle and bone health on Earth — and in humans.

Understanding the impact of Type 1 diabetes susceptibility genes
Research Spotlight

Understanding the impact of Type 1 diabetes susceptibility genes

September 17, 2020

Starting in eighth grade, a series of mentors who saw something special in Sharifa Love–Rutledge helped her stay on the path to being a researcher — and becoming a mentor to others.

Re-creating coagulation in a lab
Journal News

Re-creating coagulation in a lab

September 15, 2020

Threatened arthropods are in the crossfire of medical and conservation efforts, but new research could benefit horseshoe crabs and humans alike.