Decoding RNA splicing pathology: Alternative splicing in amyotrophic lateral sclerosis and its therapeutic potential

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron degeneration.
• RNA metabolism and splicing dysregulation are increasingly recognized as central mechanisms in ALS pathogenesis.
• Key genes like TARDBP, FET proteins, SOD1, and C9orf72 are implicated in RNA processing and transport, with mutations leading to neuronal dysfunction.

Purpose of the Study:

• To provide a comprehensive overview of RNA splicing regulation, spliceosomal dysfunction, and cryptic exon incorporation in ALS.
• To elucidate the interplay between splicing defects, RNA-binding protein pathology, and neuronal degeneration.
• To highlight advancing therapeutic strategies targeting these RNA-centric mechanisms.

Main Methods:

• Review of current literature on ALS pathogenesis, focusing on RNA metabolism and splicing.
• Analysis of the roles of specific genes (TARDBP, FET proteins, SOD1, C9orf72) and their associated pathologies.
• Examination of therapeutic approaches including gene therapy, antisense oligonucleotides, and stress kinase inhibition.

Main Results:

• Dysfunctional RNA processing, including aberrant cryptic exon inclusion in genes like STMN2 and UNC13A, contributes to motor neuron degeneration.
• TDP-43 pathology, C9orf72 expansions, FET protein mutations, and mutant SOD1 exacerbate neuronal toxicity through various mechanisms.
• Therapeutic interventions targeting STMN2 restoration, mutant transcript silencing, and reduction of protein aggregation demonstrate preclinical and early clinical promise.

Conclusions:

• Splicing defects and RNA-binding protein dysregulation are critical drivers of ALS.
• Targeting RNA processing and reducing toxic protein aggregation are key strategies for developing effective ALS therapies.
• Multimodal therapeutic approaches are essential for restoring RNA processing, mitigating protein toxicity, and promoting motor neuron survival in ALS.