Category: Research

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.

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. 

What makes it possible for cancer cells to spread and flourish despite radiotherapy, surgery to remove the initial tumor, chemotherapy and immunotherapy?

Cancer cells may be brainless, but they are as clever as chess players who want to win. They know how to spread (metastasize) to other parts of the body. It is this “skill” that makes malignant tumors the most common cause of death in Israel.

But what makes it possible for such cells to spread and flourish despite radiotherapy, surgery to remove the initial tumor, chemotherapy and immunotherapy?

A novel explanation 

Researchers at the Technion-Israel Institute of Technology in Haifa have just published an article on the subject in iScience, an interdisciplinary open-access journal with continuous publication of research across the life, physical, and earth sciences, titled “Cancer progression as a learning process.”

Aseel Shomar, a Nazareth-born doctoral student in biochemical engineering who is on an Adams Fellowship, together with Prof. Omri Barak and Prof. Naama Brenner, suggested a novel explanation in the hope that better understanding should lead to better treatment. 

They propounded the idea that cancer cells are able to learn and adapt to changing environments by actively searching for solutions that would enable them to survive. Studying cancer using this approach and tools of learning theory will advance our understanding of these phenomena, they said.

It is commonly thought that both drug resistance and the ability to metastasize appear in cancer cells as random mutations. Since such a mutation gives cancer cells an advantage, making it possible for them to survive in an environment that struggles to fight them, these mutations become dominant. 

However, mounting evidence from research groups around the world does not seem to match this hypothesis, and treatment plans based on it did not significantly increase patients’ life expectancy.

But now, the Technion team members have proposed a new hypothesis that matches the evidence at hand: cancer cells learn and adapt to their environment, enabling them to develop drug resistances and conform to the new environments of metastasis locations.

How does a cell learn without a brain? Brenner explained that when sensing stress, the cell seeks to reduce that pressure and launches a trial-and-error process within the gene regulatory network, changing the way existing genes are expressed. An interaction that reduces the stress gets strengthened.

Even so, considering the number of possible configurations the cell can try, it seems unlikely that the process would work. However, using computer simulations based on learning theory, the group showed that cells could in fact learn and adapt in this fashion. 

One element of what makes this feasible is that more than one solution can be found to solve the same problem faced by the cell. Another element is the way the gene regulatory network is structured, with regulatory “hubs” that control parts of it.

Malignant cells are not unique in their learning ability, they said. Brenner, Prof. Erez Braun and others have shown in the past that yeast cells can adapt to new environments and develop abilities they did not initially possess.

Few other labs around the world have demonstrated this effect in simple organisms.

A rare type of discovery

Learning theory – a process that brings together personal and environmental experiences and influences for acquiring, enriching or modifying one’s knowledge, skills, values and behavior – develops hypotheses that describe how this process takes place and provides the mathematical tools to study these phenomena.

The Technion’s Network Biology Research Lab studies the way various biological systems adapt, which is a process that is not fully understood.

Its researchers – who come from a variety of faculties including physics, electrical and computer engineering, chemical engineering and medicine – seek to connect theoretical models to complex and dynamic biological systems.

While tumors that learn and adapt might sound alarming, the Haifa authors were optimistic. While cancer cells have the capacity for learning, normally something holds it back. 

In fact, the same mutations found to promote cancer in our body can be carried by cells that still remain healthy. Even cells from active tumors that wander into healthy tissue were in some experiments “cured,” reverting to their non-cancerous state.

“There is an interaction between the individual cell and the tissue,” Brenner noted. “The cell has the capacity to explore, but the tissue imposes order and stability. We propose that using the approach and methods of learning theory will help investigate this interaction in greater depth. 

“Cancer could perhaps be treated through strengthening the tissue’s ability to calm and control the pre-cancerous cell.”

Most scientific studies add a brick to build the wall of discovery, but this finding is one of a rare type that reexamines existing data and proposes a new framework, offering answers to questions that had until now remained unanswered and opening up new avenues of exploration, they concluded.