Molecular analyses offer insights into novel ALS therapy approaches

Discovery of sex differences, subtypes may lead to more personalized medicine

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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New research into the molecular underpinnings of amyotrophic lateral sclerosis (ALS) has uncovered sex differences and disease subtypes, which could inform the development of new and more targeted treatment strategies.

Comprehensive analyses of ALS brain tissue samples and mouse models also identified the MAPK/ERK cell signaling pathway as a possible therapeutic target.

“We believe that our study made an important contribution in the search for causes and therapies for ALS,” Paul Lingor, MD, of the Technical University of Munich in Germany and the study’s senior author, said in a university press release. “Our findings have brought us a good deal closer to a more personalized and therefore more effective therapy.”

The study, “Multiomic ALS signatures highlight subclusters and sex differences suggesting the MAPK pathway as therapeutic target,” was published in Nature Communications.

ALS is a complex neurodegenerative disease for which the exact molecular underpinnings are poorly understood. A better understanding of these factors could aid in the development of better treatment strategies.

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‘Multi-omics’ incorporates several different data types

In the study, the researchers performed a comprehensive “multi-omics” analysis to better understand the molecule architecture of ALS. Multi-omics incorporates several different data types — including gene, protein, and other analyses — to identify disease-associated pathways.

Scientists performed the analysis on postmortem brain tissue from 51 ALS patients and 50 healthy people. Tissue from four different mouse models of ALS was also analyzed.

Results showed clear sex differences in ALS. Specifically, there were significantly more gene activity changes in men with ALS, compared to healthy people, than in women with ALS, with changes seen across a range of molecular pathways.

The findings are aligned with the higher prevalence of ALS in men, according to the researchers. It could also ultimately mean that men and women with ALS would benefit from different treatment approaches, they noted.

Moreover, the analysis revealed four distinct groups of ALS patients that differed in the specific molecular pathways that were dysregulated.

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‘Very different things happen at the molecular level’

“You can’t distinguish between these variants based on the clinical symptoms,” Lingor said. “However, very different things happen at the molecular level.”

Among the groups, one showed abnormal activation of inflammation and immune pathways, while two others were characterized by signs of oxidative stress, a type of cell damage implicated in ALS. The fourth group was characterized by problems in converting information in DNA into RNA, an intermediate molecule used to produce functional proteins.

Differences observed in brain tissue from ALS patients were also partially recapitulated in the mouse models across a series of experiments.

Again, the findings could have significant treatment implications, with some medications being possibly helpful in one ALS subtype but ineffective in another.

“Previous clinical studies were only able to look at the effects across all patients and may not have identified substances effective for an individual subtype,” Lingor said.

Through all of the human tissue and mouse experiments, the researchers identified that ALS was associated with alterations in the MAPK/ERK signaling pathway, which plays a variety of roles in cell growth, survival, and death — and several ALS-associated processes. Notably, there also appeared to be differences in these pathways by sex and ALS subtypes.

“Overall, many of the analyzes pointed towards a significant role of the MAPK pathway in ALS,” the researchers wrote.

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Cancer medication trametinib could possibly be repurposed for ALS

No approved ALS therapies target this pathway, but there’s a medication called trametinib used for certain cancers that could possibly be repurposed, according to the team.

Treatment with trametinib in a mouse ALS model was associated with reductions in disease-associated proteins and led to substantial neuroprotection in female mice, which had a later disease onset and significantly improved survival compared with untreated mice.

“Overall, our study contributes towards unraveling the complexity of ALS and lays the groundwork for further research in the field,” the researchers wrote.

In future studies, the researchers want to confirm their findings from patient tissue and mouse models in people living with ALS.

“An important next step is to find a way to determine the ALS subtype of patients while they are still alive — we are currently working on this,” Lingor said.