Structure of TDP-43 Protein Clumps Identified for First Time

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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A team of scientists in the U.K. and Japan has determined the structure of aggregated TDP-43, the protein whose abnormal clumps are characteristic of amyotrophic lateral sclerosis (ALS).

Their work, reportedly the first to reveal the molecular structure of aggregated TDP-43, identified a “double-spiral fold” of the protein in patients’ brain tissue.

“There are no diagnostics or therapeutics for ALS and other diseases associated with TDP-43 and the first step towards developing these is gaining a better understanding of TDP-43 itself,” Benjamin Ryskeldi-Falcon, PhD, a researcher with the Medical Research Council (MRC) Laboratory for Molecular Biology in Cambridge and a study co-author, said in a press release.

“Now that we know what the structure of aggregated TDP-43 looks like and what makes it unique, we can use it to find better ways to diagnose the disease early,” Ryskeldi-Falcon said.

Findings were in the study, “Structure of pathological TDP-43 filaments from ALS with FTLD,” published in Nature.

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Abnormal aggregates, or clumps, of the TDP-43 protein in nerve cells of the brain are a hallmark of ALS, and are believed to directly contribute to neurodegeneration in the disease. TDP-43 aggregates also are seen in frontotemporal dementia (FTD), a related disorder, and in other neurological diseases like Parkinson’s and Alzheimer’s.

Given its central role in disease, aggregated TDP-43 could theoretically be useful as a diagnostic marker and treatment target. However, the exact molecular structure of aggregated TDP-43 is unknown, which has hampered efforts to find clinical applications based on this protein.

Scientists analyzed aggregated TDP-43 extracted from the donated brains of two ALS patients with FTD. Using a technique called cryo-electron microscopy, they deduced the structure of the aggregates with a resolution of up to 2.6 angstroms. One angstrom is equal to one hundred-millionth of a centimeter.

Results showed that the TDP-43 aggregates took on a shape that the researchers described as a “double-spiral-shaped fold,” which has not been described previously. Aggregates from different brains areas, and between the two patients, all were similarly shaped.

“That the fold is shared between individuals suggests that the double-spiral fold may characterize ALS” and FTD, the researchers wrote.

They noted that the shape is likely to contribute to the “prion-like” spread of TDP-43 clumps, where aggregates in one part of the brain prompt more aggregates to form in neighboring regions.

“The presence of the double-spiral fold in both frontal and motor cortices is consistent with the prion-like propagation of TDP-43 filaments during … spread and accumulation of aggregated TDP-43 in ALS,” the researchers wrote.

The structure of the TDP-43 aggregates from patients’ brains also differed from previously reported structures of these protein aggregates when formed in vitro (in lab dishes).

“It will be important to produce filaments in vitro that recapitulate the double-spiral fold to accurately model ALS,” the researchers wrote. Understanding the structure of these protein clumps, they added, could also be useful for developing new ways of diagnosing and treating ALS.

“We’re excited to be able to use this blueprint in our lab to start identifying compounds that bind to unique sites on TDP-43, with the aim of identifying potential therapies for further study,” Ryskeldi-Falcon said.

“I would especially like to thank the people with ALS, and their families, who donated their brains to research to help us gain a better understanding of this terrible disease,” he added.