Mechanisms and Therapeutics in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is characterised by progressive degeneration of upper and lower motor neurons, leading to muscle weakness, spasticity and respiratory failure. Pathogenic mechanisms converge on protein misfolding, impaired RNA metabolism, mitochondrial dysfunction and neuroinflammation. Aggregation of TDP-43 and FUS proteins disrupts RNA processing, while hexanucleotide repeat expansions in C9orf72 give rise to RNA foci and dipeptide repeat proteins via repeat-associated non-ATG translation. Dysregulated autophagy and proteasome pathways further compromise cellular proteostasis. Glutamate excitotoxicity, oxidative stress and aberrant axonal transport contribute to cytoskeletal damage and synaptic dysfunction. Therapeutic development has historically focused on small molecules such as riluzole and edaravone, which confer modest survival benefits. Novel immunomodulatory strategies aim to restore regulatory T-cell homeostasis and ameliorate inflammation. Gene-targeted approaches include antisense oligonucleotides against SOD1 and C9orf72 transcripts, while stem-cell-based therapy seeks neuronal replacement and trophic support. Biomarker-driven stratification and adaptive trial platforms are increasingly essential to address clinical heterogeneity. Advances in high-resolution genomics, proteomics and machine-learning techniques promise to refine risk prediction, elucidate disease subtypes and accelerate personalised interventions, thereby shifting the therapeutic paradigm from symptomatic relief to mechanistic correction.

Research from Nature Portfolio

Recent studies have harnessed deep learning to interrogate the complex genetic architecture of ALS. A capsule-network-based model was developed to predict disease risk from whole-genome variant profiles by capturing hierarchical and non-linear interactions among loci. This approach achieved high predictive accuracy for ALS occurrence, outperforming linear methods, while identifying novel candidate genes that may underlie missing heritability. By requiring less training data to reach optimal performance, such models offer a scalable route to integrate large-scale genomic data with phenotypic outcomes. These findings highlight the potential of advanced artificial-intelligence frameworks to reveal multi-gene contributions and inform the design of precision-medicine strategies in ALS.

Mechanisms and Therapeutics in Amyotrophic Lateral Sclerosis publication trend

The graph below shows the total number of articles in mechanisms and therapeutics in amyotrophic lateral sclerosis across all publications each year (not limited to Nature Index journals).

Technical terms

Motor neuron: A nerve cell that transmits signals from the spinal cord or brainstem to muscles, controlling voluntary movement.

C9orf72 repeat expansion: A pathogenic GGGGCC hexanucleotide expansion in the C9orf72 gene that produces RNA foci and dipeptide repeat proteins.

Repeat-associated non-ATG (RAN) translation: A non-canonical translation mechanism generating proteins from nucleotide repeats without an AUG start codon.

TDP-43: TAR DNA-binding protein 43, an RNA-binding protein that forms cytoplasmic aggregates in most ALS cases, impairing RNA processing.

Neurofilament light chain (NfL): A cytoskeletal protein released during axonal damage, measurable in blood and cerebrospinal fluid as a biomarker.

Regulatory T cell (Treg): A subtype of T lymphocyte that suppresses immune activation and maintains tolerance, implicated in ALS-related neuroinflammation.

Necroptosis: A form of programmed necrosis mediated by receptor-interacting kinases, implicated in motor neuron death through non-cell-autonomous toxicity.

Capsule network: A deep learning architecture designed to preserve hierarchical relationships among features, used to model complex genetic interactions.

References

1. Efficacy and safety of low-dose IL-2 as an add-on therapy to riluzole (MIROCALS): a phase 2b, double-blind, randomised, placebo-controlled trial. The Lancet (2025).
2. Predicting the prevalence of complex genetic diseases from individual genotype profiles using capsule networks. Nature Machine Intelligence (2023).
3. Neurofilament light chain. Neurology (2015).
4. Antisense transcripts of the expanded C9ORF72 hexanucleotide repeat form nuclear RNA foci and undergo repeat-associated non-ATG translation in c9FTD/ALS. Acta Neuropathologica (2013).
5. ALS Genetics, Mechanisms, and Therapeutics: Where Are We Now?. Frontiers in Neuroscience (2019).
6. Protein aggregation in amyotrophic lateral sclerosis. Acta Neuropathologica (2013).
7. Confirmatory double-blind, parallel-group, placebo-controlled study of efficacy and safety of edaravone (MCI-186) in amyotrophic lateral sclerosis patients. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration (2014).
8. Necroptosis Drives Motor Neuron Death in Models of Both Sporadic and Familial ALS. Neuron (2014).
9. The C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy. The EMBO Journal (2016).