Unravelling the genetic overlap between sporadic ALS and C9orf72-related ALS: a comprehensive comparative investigation

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating and incurable neurodegenerative disease characterized by progressive degeneration of motor neurons, leading to muscle weakness and paralysis. Similarly, frontotemporal dementia (FTD) is another neurodegenerative disorder that affects behavior, language, and executive function. Despite extensive research efforts, the transition from diagnosis to prognosis in ALS and FTD has been slow, indicating an incomplete understanding of the underlying pathophysiological processes. One of the most prevalent causes of ALS and FTD is the hexanucleotide GGGGCC repeat expansion (HRE) within the C9orf72 gene. Sporadic ALS (sALS) and C9orf72-related ALS (C9ALS) represent two distinct yet interconnected facets of the complex landscape of ALS research. sALS, the most common form of ALS, lacks a clear genetic basis and typically occurs in individuals with no family history of the disease. In contrast, C9ALS is characterized by a hexanucleotide repeat expansion in the C9orf72 gene, rendering it the most prevalent known genetic cause of both ALS and frontotemporal dementia (FTD). This mutation has significantly reshaped our understanding of ALS pathogenesis, shedding light on the importance of repeat-associated mechanisms, RNA toxicity, and di-peptide repeat proteins. The goal of this study was to identify the biomarker common in sALS and C9ALS.METHODS: The objective of this study was to delineate and spatially map variations in gene expression signatures between the cerebellum and frontal cortex in individuals with Sporadic ALS (sALS) and C9orf72-associated amyotrophic lateral sclerosis (C9ALS). The aim was to investigate the network characteristics of these genes showing differential expression and to pinpoint microRNAs that target the shared set of genes exhibiting differential expression across both tissues and disease subset. Through this investigation, the study sheds light on the distinct susceptibilities of different cell types to the pathological mechanisms underlying sALS and C9ALS, thereby providing insights into the selection of potential therapeutic targets for the disease.RESULTS: A total of 18 common genes were identified in cerebellum and 55 common genes were identified in frontal cortex region between C9-ALS and sALS patient samples suggesting some inter-relation between the ALS-subtypes. The commonly identified genes were functionally enriched in DNA binding, RNA polymerase II transcription factor activity, unfolded protein binding, and RNA polymerase II core promoter proximal region sequence-specific DNA binding. Furthermore, network-based analysis was done to identify the hub genes in the disease-causing network. Chemical molecules based and miRNA-based drug repurposing was done to identify potential modulator for the identified potential biomarker. While sALS remains enigmatic, the insights gained from studying C9ALS offer valuable perspectives on common molecular pathways and potential therapeutic targets that could benefit a broader ALS patient population.CONCLUSIONS: Thus, investigating both sALS and C9ALS in parallel is crucial for advancing our knowledge of ALS as a whole and developing effective treatments for this devastating neurodegenerative disorder.