Nonsense-mediated RNA decay in the brain: emerging modulator of neural development and disease

Abstract

Steady-state RNA levels are controlled by the balance between RNA synthesis and RNA turnover. A selective RNA turnover mechanism that has received recent attention in neurons is nonsense-mediated RNA decay (NMD). NMD has been shown to influence neural development, neural stem cell differentiation decisions, axon guidance and synaptic plasticity. In humans, NMD factor gene mutations cause some forms of intellectual disability and are associated with neurodevelopmental disorders, including schizophrenia and autism spectrum disorder. Impairments in NMD are linked to neurodegenerative disorders, including amyotrophic lateral sclerosis. We discuss these findings, their clinical implications, and challenges for the future.

C9orf72 Dipeptide Repeats Inhibit UPF1-Mediated RNA Decay Independent of Stress Granule Formation

“…We found in c9ALS subjects an overall upregulation of numerous NMD target mRNAs as well as many noncoding RNAs including pseudogene transcripts and the splice variants of small nucleolar RNA precursors 31 (data not shown). Since many NMD factors including UPF1 are conserved in all eukaryotes and required for survival in most metazoans [32][33][34] , chronic NMD inhibition would likely be detrimental to neuronal viability 13 .…”

“…Indeed, widespread RNA processing defects have been described by previous high-throughput RNA sequencing (RNA-seq) studies using post-mortem brain tissues from both sporadic ALS (sALS) and c9ALS/FTD patients 4,11 . In normal cells, misprocessed mRNAs are targeted for degradation by multiple RNA surveillance pathways [12][13][14] , such as nonsense-mediated decay (NMD), no-go decay (NGD), and nonstop-mediated decay (NSD). The accumulation of aberrant RNAs in c9ALS/FTD brains hints at the possibility that one or more mRNA surveillance pathways may be compromised.…”

Nanopore sequencing of full-length circRNAs in human and mouse brains reveals circRNA-specific exon usage and intron retention

“…The NMD pathway is known to target mRNAs carrying a premature termination codon (PTC) in a translation-dependent manner (Belgrader, Cheng, & Maquat, 1993) and it plays a crucial role in the regulation of the transcriptome. Particularly in the brain, NMD is linked to development and neurodegenerative disorders (Jaffrey & Wilkinson, 2018;Lykke-Andersen & Jensen, 2015). The insertion of non-coding exons between coding exons in linear mRNA is likely to cause NMD, either by shifting the reading frame or by introducing a stop codon.…”

An intron proximal to a PTC enhances NMD inSaccharomyces cerevisiae

“…Additionally, by targeting functional mRNAs carrying specific features like an abnormally long 3' UTR, NMD is understood to modulate protein expression in different cellular processes, including the cell stress response and some specific cell differentiation processes (Jaffrey and Wilkinson, 2018;Nasif et al, 2018). NMD was first branded as a specific process in Saccharomyces cerevisiae (Leeds et al, 1992); its mechanism and the roles that NMD play in gene expression have extensively been studied since, in this and in several other model organisms, as previously reviewed (Fatscher et al, 2015;He and Jacobson, 2015;Hug et al, 2016;Jaffrey and Wilkinson, 2018;Karousis and Muhlemann, 2019;Kurosaki et al, 2019;Lykke-Andersen and Jensen, 2015). NMD is coupled to translation and requires a set of evolutionarily conserved proteins, including UPF1, UPF2, and UPF3 (Lloyd, 2018).…”