- Huntington’s disease and amyotrophic lateral sclerosis (ALS) are characterized by an aggregation of misfolded proteins that damage nerve cells.
- “Chaperones” are proteins that monitor and regulate protein folding and aggregation in the cell.
- A recent study has investigated the role of chaperones in the context of Huntington’s disease and ALS.
- The study found that a distinct set of chaperones could prevent the formation of protein aggregates. However, they failed to do so in Huntington’s disease and ALS.
ALS affects nerve cells that control voluntary movement, leading to muscle weakness, paralysis, and eventually death. There are currently no treatments or cures.
Like other neurodegenerative diseases, such as Alzheimer’s and Huntington’s disease, ALS is also characterized by the accumulation of misfolded proteins in the brain.
Misfolding of proteins commonly occurs in healthy cells, and molecular chaperones, a class of proteins in cells, can regulate and prevent misfolding and accumulation.
However, in cases of neurodegenerative disorders, including ALS, the mechanisms underlying the accumulation of misfolded proteins remain poorly understood, posing a challenge to the development of therapeutic interventions.
A recent study, published in the journal
The study’s lead author, Dr. Reut Shalgi, a professor of nano biotechnology and nanomedicine at Technion – Israel Institute of Technology, told Medical News Today:
“Our study shows that cells have the toolkit to combat pathological aggregation related to ALS, and this is already encoded in the genome. We found that there are different tools, i.e., chaperones, that are optimized to handle and prevent pathological aggregates of different types.”
“Unfortunately,” she continued, “our cells just don’t know how to activate the specific toolkit that is needed for each different type of pathological aggregate.”
“Identifying the optimal toolkit to fight aggregation in each disease type and understanding how they work, as we have done here, is only the first step.”
During protein synthesis, amino acids become linked together in a linear chain. This chain of amino acids subsequently undergoes folding to acquire a three-dimensional structure, forming a biologically active protein.
This three-dimensional configuration is essential for the protein to perform its biological function.
Chaperones are a class of proteins produced by cells that assist with the proper folding of other proteins. Moreover, chaperones can also facilitate the refolding or degradation of misfolded proteins and prevent the aggregation of proteins.
This function of chaperones is critical, as protein misfolding and aggregation can damage cells.
Neurodegenerative diseases, such as Alzheimer’s disease, Huntington’s disease, and ALS, are characterized by the formation of aggregates of specific proteins.
Previous studies have shown that certain chaperones can prevent the aggregation of the Huntingtin protein. Chaperones belonging to the HSP70 network have a protective effect against aggregation of this protein.
The HSP70 network consists of the HSP70 family of proteins and chaperones belonging to the HSP40/DNAJ family. The proteins in the HSP40 family help regulate the activity of the HSP70 proteins.
However, there has been limited research into chaperones that could protect against the aggregation of ALS-related proteins, such as the FUS protein. The present study characterized and compared chaperones that could protect against the formation of protein aggregates involved in Huntington’s disease and ALS.
Both Huntington’s disease and ALS are characterized by mutations in respective proteins that form aggregates.
In the new study, the researchers used laboratory cultured cells expressing the mutant Huntingtin and FUS proteins to characterize chaperones that could prevent protein aggregation.
The researchers first characterized the differences in the expression of genes for chaperone proteins in cells expressing these mutant proteins.
In cells expressing the mutant Huntingtin protein, the researchers found increased expression of genes for chaperone proteins, including those belonging to the HSP70 family and other stress proteins.
In other words, these results suggest that the cells responded to misfolded Huntingtin protein by activating a stress response.
In contrast, there was a decline in the levels of the HSP70 proteins in mutant FUS-expressing cells. Chaperone proteins play an important role in maintaining an equilibrium between the synthesis, folding, and degradation of proteins.
The lower levels of chaperone proteins in mutant FUS-expressing cells thus suggest a disruption of this equilibrium.
The researchers then investigated if there were chaperones that could repress the aggregation of the mutant Huntingtin and FUS proteins.
To more specifically identify chaperones that could prevent the aggregation of the Huntingtin and FUS proteins, the researchers used cultured cells expressing either the mutant Huntingtin or FUS protein and a specific chaperone protein.
They induced the cells to express each of a selection of 66 chaperones, which included proteins from the HSP70 network.
The researchers found that specific chaperones facilitated the formation of mutant Huntingtin protein aggregates, whereas others protected against the accumulation of such protein aggregates.
They obtained similar results for the mutant FUS proteins. The groups of chaperones that facilitated or inhibited the aggregation of the mutant FUS protein were distinct from the corresponding chaperones modulating the formation of Huntingtin aggregates.
Some chaperone proteins exist in two forms, a full-length version (-FL) and a shortened version (-short). The researchers found that the DNAJB12-short protein prevented the formation of the Huntingtin protein aggregates, whereas the DNAJB12-FL promoted the aggregation of the Huntingtin protein.
A chaperone belonging to the HSP70 family, Hspa6, also enhanced the formation of Huntingtin protein aggregates. Moreover, the results from the initial gene expression experiment suggested upregulation of the HSP70 family in cells expressing the Huntingtin protein.
In other words, the cells produced a maladaptive response by expressing certain HSP70 family proteins, such as Hspa6, that enhance protein aggregation in response to the expression of the mutant Huntingtin protein.
In cells expressing the mutant FUS protein, DNAJB14 chaperone protein reduced the levels of aggregates. In contrast, certain chaperones, such as the DNAJB5 chaperone protein, enhanced the aggregation of the mutant FUS protein.
Similar to the DNJAB12 protein, DNAJB14 also exists in short and full forms. The researchers found that the formation of a complex between DNAJB14-FL and DNAJB12-FL was necessary to prevent the aggregation of mutant FUS protein.
Also, these protective effects of the DNAJB14-DNAJB12 complex were mediated through its interaction with the HSP70 protein.
The researchers also found that the short forms of DNAJB14 and DNAJB12 did not become a complex or interact with HSP70, thus lacking a protective effect against the mutant FUS protein aggregates.
These results are unlike those obtained with the mutant Huntingtin protein, where the short form of DNAJB12 enhanced the formation of aggregates.
The researchers then investigated how DNAJB14 protected cells from the aggregation of the mutant FUS protein. In the initial gene expression experiment, the researchers found that the expression of genes for chaperones belonging to the HSP70 family was repressed in cells with mutant FUS protein aggregates.
In a subsequent experiment, they found that the expression of DNAJB14 normalized the expression of genes encoding chaperones belonging to the HSP70 and other families.
The authors noted that the interaction of the DNAJB14-DNAJB12 complex with the HSP70 protein was necessary to prevent the aggregation of mutant FUS protein, but the expression of the HSP70 gene was repressed in cells expressing the mutant FUS protein.
Thus, as seen with the Huntingtin protein, although the cells were capable of producing chaperones that could counter the formation of the mutant FUS protein aggregates, they failed to produce the required adaptive response in response to the aggregates.
“In the future,” Dr. Shalgi told MNT, “we hope to develop tools that will facilitate the activation of the right toolkit for each of these aggregates, toward helping patients fight these aggregates, and move toward disease-modifying therapies for ALS and other neurodegenerative diseases.”