Serum small non-coding RNA define molecular subtypes in amyotrophic lateral sclerosis

Area of Science:

• Biochemistry
• Genetics
• Neuroscience

Background:

• Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with variable onset and progression.
• Diagnostic delays in ALS are common due to overlapping early symptoms with other neurological conditions.

Purpose of the Study:

• To identify tRNA-derived small RNAs (tsRNAs) and microRNAs (miRNAs) as potential serum biomarkers for ALS diagnosis.
• To compare small non-coding RNA (sncRNA) profiles in ALS patients, healthy controls, and ALS mimics.
• To gain pathophysiological insights from dysregulated sncRNAs and identify ALS molecular subtypes.

Main Methods:

• Small RNA sequencing (small RNA-seq) was performed on samples from 158 ALS patients, 60 healthy controls, and 39 ALS mimics.
• An extreme gradient boosting (XGBoost) classifier was developed to evaluate the diagnostic potential of identified sncRNAs.
• Hierarchical clustering and gene ontology/pathway analysis were used to identify ALS molecular subtypes and disrupted pathways.

Main Results:

• Several dysregulated tsRNAs and miRNAs were identified, showing potential as diagnostic biomarkers.
• The XGBoost classifier achieved high accuracy (87.16% for ALS vs. controls, 82.23% for ALS vs. mimics).
• Four sncRNA expression-based ALS molecular subtypes were identified, including one enriched for C9orf72, with dysregulated sncRNAs involved in neuronal pathways.

Conclusions:

• Dysregulated sncRNAs in serum show potential as diagnostic biomarkers for ALS.
• Identification of sncRNA-based molecular subtypes offers avenues for further research into subtype-specific biomarkers and therapies.
• This study provides a foundation for developing improved diagnostic tools and targeted therapeutic strategies for ALS.