Integrating single-cell transcriptomics into model systems to decode neurodegeneration in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by motor neuron degeneration. Several genetic risk factors, including mutations in C9orf72 , SOD1 , TARDBP and FUS have been linked to disease. However, the precise cellular pathogenic mechanisms of ALS remain poorly understood, impeding the development of effective therapeutics. ALS model systems, ranging from Drosophila , mice to human induced pluripotent stem cells (hiPSCs), are powerful research platforms for decoding these mechanisms, with their high genetic tractability allowing for the tracking of disease across the life course. Recently, the application of single cell resolution approaches have allowed the dissection of the heterogenous nature of cellular response to disease in these models, revealing novel ALS pathogenic mechanisms and therapeutic targets. In this Review, we explore the unique benefits and challenges of using single-cell RNA-sequencing (scRNA-seq)/single-nucleus RNA-sequencing (snRNA-seq) analysis of in vivo and in vitro ALS model systems to identify disease pathways and drive our mechanistic understanding of ALS forward. By using single cell approaches in models of ALS, researchers can identify novel, druggable, cellular pathways acting across all disease stages that may be obscured in late-stage post-mortem tissue.