TDP-43 more likely to clump if it can’t form two-protein complexes

ALS research into toxic aggregates found in about 97% of patients

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Nerve cells are shown in this illustration.

When the TDP-43 protein is less able to form two-protein complexes called dimers, it appears to be more likely to form the toxic clumps seen in amyotrophic lateral sclerosis (ALS), a study reports.

As these clumps are found in about 97% of all ALS cases, a better understanding of the mechanisms leading to TDP-43 protein aggregates may help in developing therapies for most patients.

“Maintaining the … equilibrium of these pathogenic proteins may represent a common therapeutic target for neurodegenerative diseases,” its researchers wrote.

The study, “Monomerization of TDP-43 is a key determinant for inducing TDP-43 pathology in amyotrophic lateral sclerosis,” published in Science Advances.

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Research into how TDP-43 aggregates in nerve cells of ALS patients

One of the key molecular features of ALS is the abnormal aggregates — clumps — of the protein TDP-43 in nerve cells. This protein normally is found in the nucleus — the cellular compartment that houses DNA — but in virtually all ALS cases, the protein instead forms aggregates outside the nucleus.

It’s thought that TDP-43 clumps disrupt normal nerve function and contribute to driving the disease. Exactly how these clumps form, however, remains incompletely understood.

Under normal circumstances, TDP-43 is found in two states in nerve cells. Either the protein exists as a monomer containing just one TDP-43 protein, or the protein exists in a dimer where two of the proteins are attached to each other.

Scientists set out to investigate whether changes in the monomer/dimer status of TDP-43 is disrupted in ALS, and whether such changes may play a role in the protein’s abnormal clumping.

They first conducted tests on nerve tissue collected from people with sporadic ALS. Results showed that these tissues had more TDP-43 monomers, and correspondingly fewer dimers, than what’s normally seen in people without the disease.

More TDP-43 in its monomer state might help to trigger ALS-related molecular changes, findings implied. To test this idea, the researchers engineered nerve cells harboring a modified version of the TDP-43 protein — one not able to form dimers, so it only exists as a monomer unless it’s forming clumps.

Experiments in these cells showed that, when TDP-43 is only present as a monomer, it’s more likely to move outside of the nucleus into the cytoplasm and clump.

Lack of TDP-43 ‘monomer-dimer equilibrium’ may occur early in ALS

Further experiments revealed clues as to the biochemical processes underlying these changes. Dysregulations in transcription — the initial process where a cell “reads” a gene — can lead to more TDP-43 in monomer form, the researchers found. The movement of TDP-43 from the cell nucleus to the cytoplasm also was seen to be regulated by another protein called Nxf1.

“TDP-43 monomerization induced its cytoplasmic mislocalization in an Nxf1-dependent manner, along with … aggregation of TDP-43, which is a pathological hallmark of ALS,” the scientists wrote.

These findings “may be important in future research on early pathogenic [disease-causing] events related to TDP-43 and in the search for early diagnostic markers,” they added.

“Our study showed that the disruption of TDP-43 monomer-dimer … equilibrium may be a relatively early change, followed by cytoplasmic mislocalization of monomeric TDP-43, leading to … sequestering of normal TDP-43 into aggregates,” the scientists concluded. “We speculate that this vicious cycle may exacerbate TDP-43 pathology.”