summary: Researchers have identified four subtypes of ALS that may lead to more effective, personalized treatments. The study also revealed striking molecular differences between male and female ALS patients.
A promising drug target, the MAPK signaling pathway, has been identified, potentially leading to new therapeutic approaches. These discoveries bring us one step closer to understanding and treating this fatal neurodegenerative disease.
Key Facts:
- The four subtypes of ALSALS can be divided into subtypes with different molecular mechanisms.
- Gender differencesSignificant molecular differences were found between male and female ALS patients.
- Drug TargetsThe MAPK signaling pathway is a promising target for new ALS treatments.
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Amyotrophic lateral sclerosis, or ALS for short, is a mysterious neurodegenerative disease that is almost always fatal.
A consortium of researchers led by the Technical University of Munich (TUM) has systematically investigated the molecular mechanisms underlying ALS. In particular, the team discovered that ALS can be divided into subtypes.
Depending on the subtype, different drugs may be effective. There are also clear differences in molecular processes when comparing men and women. Moreover, researchers have identified promising targets for new drugs against ALS.
The molecular processes in the body that lead to the gradual loss of control of motor function in ALS patients are still not fully understood, and research to date has been limited to individual aspects of the underlying molecular processes.
The consortium, led by neurologist Professor Paul Lingol at TUM, investigated ALS using a so-called “multi-omics” approach: the researchers mapped both coding and non-coding RNA molecules, as well as whole proteins.
Four subtypes
The main finding of this study is that ALS can be broadly categorized into four subtypes.
“You can’t tell these mutations apart based on clinical symptoms,” says Paul Lingol, who is part of the SyNergy Cluster of Excellence, which, along with other researchers, studies neurodegenerative diseases.
“However, something completely different happens at the molecular level. That means that an active substance that is ineffective against one ALS subtype may be effective against another. Previous clinical studies have only looked at the effects on all patients, and may not have been able to identify substances that are effective against individual subtypes.”
One of the common subtypes affected genes related to inflammatory processes and immune responses, while another subtype showed mainly defects in the transcription of DNA into RNA molecules. The other two subtypes showed different signs of oxidative stress in cells. The researchers believe that ALS subtypes may change over the course of the disease.
Promising drug discovered
Men develop ALS about 1.2 times more often than women. A breakdown of the molecular processes also revealed clear differences between the sexes: While the four subtypes appear to occur equally frequently in both sexes, researchers found a significantly higher number of mutated gene products in men.
From a researcher’s perspective, this may mean that men and women will need to be treated differently in the future.
Through their multi-omic analysis, the researchers also identified signaling pathways that may be particularly suitable targets for new drugs against ALS.
“This signalling pathway, MAPK, is well described in neurobiology and plays a role in various (but by no means all) processes in ALS,” says Professor Stefan Bonn, last co-author of the study and Director of the Institute of Medical Systems Biology at the University Medical Center Hamburg-Eppendorf (UKE).
Therefore, from a researcher’s perspective, repurposing approved anticancer drugs that act on MAPK for ALS seems promising.
A basis for future research
The study is based on tissue samples from deceased ALS patients and additional research using mouse models of the disease.
“The next important step is to find a way to determine the ALS subtype while the patient is still alive, which is what we are working on now,” says Paul Lingall.
“We believe that our study has made an important contribution to the search for the causes and cure of ALS. Our findings bring us significantly closer to more personalized and therefore more effective treatments.”
About this ALS research news
author: Paul Helmich
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contact: Paul Helmich – TUM
image: Image courtesy of Neuroscience News
Original Research: Open access.
“Multi-omic ALS signature highlights subclusters and sex differences and suggests the MAPK pathway as a therapeutic target” Paul Ringer et al. Nature Communications
Abstract
Multi-omic ALS signature highlights subclusters and sex differences and suggests the MAPK pathway as a therapeutic target
Amyotrophic lateral sclerosis (ALS) is a debilitating motor neuron disease lacking effective disease-modifying treatments. In this study, we utilize a comprehensive multi-omics approach to investigate the early and sex-specific molecular mechanisms underlying ALS.
Analysis of the preparietal cortex of 51 sporadic ALS patients and 50 controls, together with four transgenic mouse models (C9orf72-, SOD1-, TDP-43-, FUS-ALS), revealed key molecular alterations associated with the disease, showing that males have more pronounced alterations in molecular pathways than females.
Integrated analysis of the transcriptome, (phospho)proteome and miRNAomes also identified human ALS subclusters characterized by diversity in immune response, extracellular matrix organization, mitochondrial function and RNA processing. The molecular signatures of the human subclusters were mirrored in specific mouse models.
Our study highlighted the mitogen-activated protein kinase (MAPK) pathway as an early disease mechanism.
Furthermore, the MAPK inhibitor trametinib demonstrated potential therapeutic effects in vitro and in vivo, especially in females, suggesting a direction for the development of targeted ALS therapies.