Cracking the code of ALS: How VIB researchers are leading the way
Highlighting a review series for ALS Awareness Day
For this year’s ALS Awareness Day, we are highlighting some of the research and efforts pioneered by VIB researchers, featured in a review series by The Lancet Neurology.
Decoding the Blueprint – A Map of ALS Genes
Every 21 June , we celebrate Global Amyotrophic Lateral Sclerosis (ALS) Awareness Day, and we are reminded of the urgency to answer to a disease that still has no cure. However, the past three decades have been extremely fruitful in cracking the genetic code of ALS, identifying the mutations causing motor neurons to fail.
From January to May 2025, The Lancet Neurology published a four-part review series starting from the major genetic causes of ALS: from the first and historic discovery of mutations in SOD1, to the most recent genetic insights.
Out of these four reviews, two include key contributions from labs at the VIB-KU Leuven Center for Brain & Disease Research and at VIB-UAntwerp Center for Molecular Neurology. This reflects VIB’s leading role in the global effort to understand and eventually defeat ALS.
The SOD1 Encryption
The first breakthrough of ALS’ genetic code came in 1993, with the discovery of the superoxide dismutase 1 (SOD1) gene mutations. This enzyme, although with a beneficial antioxidant role within the cell, turns toxic when mutated, misfolding and forming harmful aggregates that poison and decay motor neurons.
The first review of this four-part series, written by Benatar et al., looks back at this historical mark in ALS research, as well as therapeutic strategies that try to target this mutated enzyme for ALS alleviation over the last 30 years. It also shows how these studies laid the groundwork for genetic testing and therapeutic targeting in ALS, as well as future research studies. Finally, the review analyzes the success of tofersen, an antisense oligonucleotide drug that lowers SOD1 levels, which also marked an important proof of concept: if you can crack the mutation, you can rewrite the outcome.
The FUS Mutation Puzzle
The second part of this series had the major contributions from both Sandrine da Cruz and Ludo Van Den Bosch, group leaders and principal investigators of their respective labs, at the VIB-KU Leuven Center for Brain Disease & Research. This review segues into the mutations in the FUS gene, which encodes for a protein with a multitude of functions, primarily connected to RNA metabolism and DNA repair within cell nuclei. However, mutant FUS becomes trapped in the cytoplasm, and aggregate into toxic clumps. Although FUS mutations may only be carried by a smaller percentage of ALS patients, they cause earlier onset and faster progression compared to other forms of ALS.
This FUS review with Thomas Moens, a former post-doc of the Van Den Bosch lab as first author, sheds light on how mutated FUS disrupts cell processes such as RNA transcription and protein quality control, pointing to convergent therapeutic targets. This review also revealed shared vulnerabilities with other ALS genes, further showing that it’s not just about mutations in a single gene, like SOD1 or FUS, but about the broader dysregulated pathways within ALS.
The C9orf72 Glitch
The third part of the review series highlighted a different genetic mutation in ALS, which, in contrast to the previously described mutations, isn’t a typo, but instead a stutter.
A massive GGGGCC repeat expansion in the C9orf72 region of chromosome 9, produces rogue RNAs and dipeptide repeat proteins (DPRs) that clog and derail cellular systems. This review, led by VIB-UAntwerp Center for Molecular Neurology’s Rosa Rademakers' lab, shows how these repeats hijack RNA-binding proteins, block nucleocytoplasmic transport, and trigger immune dysfunction. It’s a code glitch that replicates itself on multiple levels, shedding light on other forms of disease which require attention as well. Regarding this glitch, this review focused on the uniqueness of these genetic code abnormalities, studied over the past 14 years, and suggests that therapies targeting just one output haven’t been enough, suggesting we need multi-pronged tools to debug the entire glitch.
The TARDBP and TDP-43 System Errors
The fourth and final part of this review series, led by Rickie Patani, showed how other ALS-related genes, beyond SOD1, FUS, and C9orf72, point to repeated vulnerabilities within neurons: RNA metabolism, protein quality control, autophagy, and neuroinflammation. This final review highlighted how a TARDBP mutation, the gene which encodes the TDP-43 protein, shares the same cell phenotypes and disruptions as the other mutations involved in ALS.
These shared errors in the genetic code further reinforce the thought that ALS isn’t just a result of a punctual error, but instead, could be caused by a network of system errors. This convergence offers further insights, as stabilizing these shared processes, could enable us to crack the genetic code of ALS, developing broad-spectrum therapies that can help many ALS patients, regardless of mutation.
The Key to Code Solving
With high dedication, cutting-edge research, innovative models, and therapeutic strategies within their vision, researchers at VIB are helping transform genetics into hopeful results.
Although ALS may still feel like an unsolved puzzle, with each genetic discovery it becomes clearer: ALS is not beyond our understanding. Decades of important research and relentless work saw the discovery of the first SOD1 mutation, to the other genetic code dysfunctions that create different pathways where ALS begins, spreads, and breaks down neurons.
This review series showed how, both at VIB and around the world, researchers are no longer just analyzing the genetic code of ALS but rewriting it and allowing new therapies to emerge in a broader spectrum.
Perhaps in the next ALS Awareness Day we could be discussing how cracking the code for ALS has taken another step forward.
Moreover, communicating these discoveries with patients and organizations is something integral to VIB’s mission. The current ties to ALS Liga, an ALS Patient Association in Flanders, allow VIB to underscore the importance of translating research into patient-relevant outcomes.
