The neurodegenerative diseases ALS and SMA are linked at the molecular level via the ASC-1 complex

• Published in: Nucleic acids research Vol. 46; no. 22; pp. 11939 - 11951
• Main Authors: Chi, Binkai, O'Connell, Jeremy D, Iocolano, Alexander D, Coady, Jordan A, Yu, Yong, Gangopadhyay, Jaya, Gygi, Steven P, Reed, Robin
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 14.12.2018
• Subjects: Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Carrier Proteins - genetics; Carrier Proteins - metabolism; CRISPR-Cas Systems; DNA Helicases - genetics; DNA Helicases - metabolism; Gene Editing; Gene Expression Regulation; Gene Knockout Techniques; Humans; Molecular Biology; Muscular Atrophy, Spinal - genetics; Muscular Atrophy, Spinal - metabolism; Muscular Atrophy, Spinal - pathology; Nuclear Matrix-Associated Proteins - deficiency; Nuclear Matrix-Associated Proteins - genetics; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Positive Transcriptional Elongation Factor B - genetics; Positive Transcriptional Elongation Factor B - metabolism; Ribonucleoprotein, U1 Small Nuclear - genetics; Ribonucleoprotein, U1 Small Nuclear - metabolism; RNA Polymerase II - genetics; RNA Polymerase II - metabolism; RNA, Transfer - genetics; RNA, Transfer - metabolism; RNA-Binding Protein EWS - deficiency; RNA-Binding Protein EWS - genetics; RNA-Binding Protein FUS - deficiency; RNA-Binding Protein FUS - genetics; RNA-Binding Proteins - genetics; Spliceosomes - chemistry; Spliceosomes - metabolism; TATA-Binding Protein Associated Factors - deficiency; TATA-Binding Protein Associated Factors - genetics; Transcription Factors, TFII - genetics; Transcription Factors, TFII - metabolism
• ISSN: 0305-1048; 1362-4962
• DOI: 10.1093/nar/gky1093

Abstract Understanding the molecular pathways disrupted in motor neuron diseases is urgently needed. Here, we employed CRISPR knockout (KO) to investigate the functions of four ALS-causative RNA/DNA binding proteins (FUS, EWSR1, TAF15 and MATR3) within the RNAP II/U1 snRNP machinery. We found that each of these structurally related proteins has distinct roles with FUS KO resulting in loss of U1 snRNP and the SMN complex, EWSR1 KO causing dissociation of the tRNA ligase complex, and TAF15 KO resulting in loss of transcription factors P-TEFb and TFIIF. However, all four ALS-causative proteins are required for association of the ASC-1 transcriptional co-activator complex with the RNAP II/U1 snRNP machinery. Remarkably, mutations in the ASC-1 complex are known to cause a severe form of Spinal Muscular Atrophy (SMA), and we show that an SMA-causative mutation in an ASC-1 component or an ALS-causative mutation in FUS disrupts association between the ASC-1 complex and the RNAP II/U1 snRNP machinery. We conclude that ALS and SMA are more intimately tied to one another than previously thought, being linked via the ASC-1 complex.