The role of nonsense-mediated decay in neuronal ceroid lipofuscinosis

Abstract

Neuronal ceroid lipofuscinosis (NCL), commonly referred to as Batten disease, is a group of autosomal recessive neurodegenerative diseases of childhood characterized by seizures, blindness, motor and cognitive decline and premature death. Currently, there are over 400 known mutations in 14 different genes, leading to five overlapping clinical variants of NCL. A large portion of these mutations lead to premature stop codons (PTCs) and are predicted to predispose mRNA transcripts to nonsense-mediated decay (NMD). Nonsense-mediated decay is associated with a number of other genetic diseases and is an important regulator of disease pathogenesis. We contend that NMD targets PTCs in NCL gene transcripts for degradation. A number of PTC mutations in CLN1, CLN2 and CLN3 lead to a significant decrease in mRNA transcripts and a corresponding decrease in protein levels and function in patient-derived lymphoblast cell lines. Inhibiting NMD leads to an increased transcript level, and where protein function is known, increased activity. Treatment with read-through drugs also leads to increased protein function. Thus, NMD provides a promising therapeutic target that would allow read-through of transcripts to enhance protein function and possibly ameliorate Batten disease pathogenesis.

Nonsense-mediated decay in genetic disease: Friend or foe?

“…In addition to the examples given above, we have shown previously that NMD recognizes numerous mutations from a variety of genes that cause neuronal ceroid lipofuscinosis (NCL), a group of fatal neurodegenerative disorders, leading to variable gene expression and subsequent differences in protein function and clinical severity [114-116]. …”

“…These compounds have been shown in both in vitro and in vivo models to alleviate disease pathogenesis by enhancing PTC read-through [119]. Examples include cystic fibrosis (CF) [120-131], Becker and Duchenne muscular dystrophy (BMD/DMD) [128, 129, 132-140], ataxia telangiectasia [139, 141, 142], Rett syndrome (RTT) [143-146], Usher syndrome type I (USH1) [147-149], Hurler syndrome (MPS1) [150-154], Maroteaux-Lamy syndrome (MPSVI) [155], carnitine palmitoyltransferase 1A (CPT1A) [156], hemophilia [157, 158], methylmalonic acidura (MMA) [159], neuronal ceroid lipofuscinosis (NCL) [114, 160, 161], spinal muscular atrophy (SMA) [162], peroxisome biogenesis disorder (PBD) [163, 164], obesity [165], poor drug metabolism [166], and cancer [151]. …”

NMD: At the crossroads between translation termination and ribosome recycling

“…Termination codons associated with atypically long 3′-UTRs are also sufficient to elicit NMD [25–29], an observation which led to the notion that termination context dictates an mRNA’s susceptibility to NMD [30]. The broad range of transcripts encompassed as NMD substrates has substantial biological impact: not only does NMD ensure removal of “junk” (e.g., some byproducts of alternate splicing, intron-containing transcripts that enter the cytoplasm, or pseudogene mRNAs [10]), but it also effectively renders most nonsense alleles as null alleles [31, 32] and has been co-opted to regulate the levels and locations of specific proteins [33, 34]. …”

A Novel c.776_777insA Mutation in CLN1 Leads to Infantile Neuronal Ceroid Lipofuscinosis

“…CLN1 mRNA expression was also compared with a previously studied INCL cell line harboring the p.Arg151X mutation, which has been previously shown to induce nonsense-mediated decay. 19 Both of the INCL cell lines (white bars) showed a significant decrease in CLN1 expression compared to wild-type (black bar) and disease control to 5 0 exosome complex, which degrade the mRNA transcript. 23,24 The eIF4A3 protein is part of the exon junction complex, which resides 24 to 26 nucleotides upstream of every exon-exon splice site in eukaryotic mRNA.…”

“…This 1.70-fold decrease in CLN1 mRNA abundance was similar to the decrease seen in an infantile neuronal ceroid lipofuscinosis cell line that is compound heterozygous for a missense mutation (p.Tyr75His) and a nonsense mutation (p.Arg151X), which has been shown previously to induce nonsense-mediated decay. 19 Although these 2 cell lines exhibit similar CLN1 mRNA expression levels, this is not a clear indication of nonsense-mediated decay involvement. Therefore, siRNA-mediated knock-down of 2 critical nonsense-mediated decay proteins, UPF1 and eIF4A3, was performed.…”