Cells Can Break Down Protein Clumps, But Don’t Know When to Do It

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Cells contain certain chaperone proteins that can break down the protein clumps found in amyotrophic lateral sclerosis (ALS) and Huntington’s disease, but don’t always activate the right proteins at the right time, a recent study shows.

“[The cells] do not always realize there is a problem, or know how to solve it, even when they do in fact have the tools to do so,” Reut Shalgi, PhD, a professor at Technion Israel Institute of Technology and the study’s principal investigator, said in a press release.

“The good news is that since the ability is there, we hope future treatments can be developed to activate it and employ the body’s own tools to cure these debilitating neurodegenerative diseases,” Shalgi said.

The study, “Differential roles for DNAJ isoforms in HTT-polyQ and FUS aggregation modulation revealed by chaperone screens,” was published in Nature Communications

Neurodegenerative diseases, including ALS and Huntington’s, are characterized by protein aggregation (clumping) in the nerves’ cells, impairing their function.

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Normally, when a protein is made in the body, it is folded into the 3D shape it needs to perform its function. In neurodegenerative diseases, however, certain proteins fail to fold properly, and instead stick to each other, forming aggregates.

Chaperone proteins help other proteins fold into the correct shape. Sometimes, when proteins aggregate, chaperones are activated to correct the mistake.

The researchers sought to investigate the ability of specific chaperones to break down ALS or Huntington’s-associated aggregates. To do so, they tested 66 chaperones in cultures with either aggregates of the Huntington’s-related Huntingtin protein, or with FUS protein aggregates, which are found in many cases of familial ALS.

Overall, eight individual chaperones were able to prevent ALS aggregate formation, and four provided significant protection against Huntington’s aggregates, although there was no overlap between the two diseases, the researchers noted.

One chaperone that protected against ALS aggregates — DNAJB14 — exists in two versions, called isoforms. The isoforms are similar, but one is shorter and lacks some important protein domains that are present on the longer version.

The researchers found that, contrary to the long version, the short version could not break down the FUS aggregates. According to the researchers, this could be because the long isoform contains a region responsible for interacting with HSP70 proteins — an important family of chaperones — that the researchers hypothesized may be important for the protein’s ability to break down aggregates.

Indeed, when the researchers blocked the HSP70-binding domain on the long version, it also lost its ability to prevent aggregates.

In Huntington’s aggregates, another chaperone, DNAJB12, significantly worsened aggregate formation in its long isoform, but was protective in its short isoform, which also lacked the HSP70 binding domain.

Although DNAJB12 did not independently influence ALS aggregates, a physical interaction was sometimes observed between DNAJB14 and DNAJB12. When the team prevented this interaction, DNAJB14 no longer was able to clear FUS aggregates, suggesting that the interaction between the two proteins likely contributes to DNAJB14’s ability to remove aggregates.

Overall, “these results collectively support the notion that the DNAJB14–DNAJB12–HSP70 complex is essential for providing substantial protection from [ALS-associated aggregates],” the researchers wrote.

Furthermore, when DNAJB14’s long version was added to cell cultures containing FUS aggregates, the expression of more chaperones and other proteins important for maintaining protein function — which had been diminished by aggregate formation — was restored.

“This represented a fine-tuned, apparently well-suited response to address the challenges of [FUS aggregate-containing] cells,” the researchers wrote.

However, when the team compared overall production of chaperone proteins in cells with and without the protein clumps, they found that the cells with FUS aggregates failed to naturally increase levels of the protective chaperones in response to the aggregates. In fact, many chaperones, including those in the HSP70 family, were repressed.

Overall, this suggests that while cells have the tools to break down ALS aggregates, they don’t always respond properly, and may fail to activate the right chaperones at the right time.

“It is not enough that the tools exist in the cell’s toolbox. The cell needs to realize there is a problem, and then it needs to know which, out of the many tools available to it, it should use to solve the problem,” said Shalgi.

The team noted, however, that identifying the key chaperones involved provides a target for the development of future therapeutic interventions.