List of lncRNAs related to ALS. In square bracket the relative references.
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disorder characterized by the selective death of upper and lowers motor neurons in spinal cord, brain stem, and motor cortex, which leads to paralysis and death within 2–3 years of onset. Deeply sequencing technologies, to simultaneously analyze the transcriptional expression of thousands of genes, offered new possibilities to focus on ALS pathogenesis and, most notably, to find new potential targets for novel treatments. The present book chapter illustrates recent advances in transcriptomic studies in animal models and human samples and in new molecular targets related to ALS pathogenesis and disease progression. Additionally, new insights into the involvement of altered transcriptional profiles of noncoding RNAs (microRNA and lncRNA) and ALS-associated ribosomal binding proteins have been investigated, to understand the functional consequences of extensive RNA dysregulation in ALS. Attention has been also turned on how transcriptome alterations could highlight new molecular targets for drug development.
Keywords
- ALS
- RNA metabolism
- transcriptomics
- gene expression
- noncoding RNA
1. Introduction
Aberrant RNA metabolism is one of the major contributors to ALS pathogenesis.
Understanding RNA-binding protein functions and identifying target RNA regulatory networks is crucial to deepen ALS knowledge and to develop new therapeutics.
miRNAs are strongly linked to the development of ALS and are indicated as new potential biomarkers.
lncRNAs have been recently indicated to play important roles in CNS in health and disease such as ALS.
miRNA-based therapeutics as well as deregulated AS are considered important areas for therapeutic intervention.
Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disorder (ND) that affects the human motor system, that is, the lower and upper motor neurons (MNs). Among the symptoms of ALS, there are progressive muscle weakness and paralysis, swallowing difficulties, and breathing impairment due to respiratory muscle weakness that finally causes death, within 2–5 years following clinical diagnosis [1]. Now, also extramotor systems are involved in ALS, thus providing new insight into the pathogenesis of the disease. So far, no effective therapy is available for ALS: Rilutek (riluzole) and Radicava (edaravone) are the only two drugs approved by the Food and Drug Administration for ALS treatment. Unfortunately their effect in slowing disease progression is very modest [2]. The majority of ALS cases, named as sporadic (sALS), has no a family history; a fraction of cases (about 5–10%) are considered familial (fALS) [3], because of mutations in genes involved in a wide range of cellular functions. 60–70% of fALS and 10% of sporadic ALS (sALS) cases can be ascribed to mutations in SOD1, TARDBP, FUS, VCP, C9ORF72, and OPTN [4]; further rare genetic variants have also been identified, MATR3, HNRNPA1, HNRNPA2/B1, EWSR1, TAF15, ANG, UBQLN2, VAPB, TBK1, SQSTM1, PFN1, TUBA4A, KIF5A, ANXA11, and CHCHD10 [5]. Although an in-depth understanding of the mechanisms underlying ALS has yet to be reached, a growing interest was addressed to the impairment of RNA metabolism as one of the major contributor to ALS pathogenesis. This concept is reinforced by the discovery of genetic mutations in FUS and in TARDBP genes coding for RNA binding proteins (RBPs), which play a multifaceted role in transcription and in maintaining RNA metabolism. Recent studies have reported that a substantial portion of the genome is actively transcribed as noncoding RNA molecules. These noncoding RNAs are fundamental key actors in the regulation of biological processes and function as a “fine switch” of gene expression. It is now recognized that dysregulations in the noncoding RNAs gene expression is a putative mechanism in several neurological disorders, including ALS. Moreover, noncoding RNAs are emerging as new potential biomarkers contributing to an early disease diagnosis and treatment follow-up. To date, miRNA have been one the main focus of most ALS studies. miRNAs are differentially expressed in several tissues (CSF, plasma and serum) in ALS patients compared to healthy controls.
In this chapter, we will focus on the involvement of altered transcriptional profiles of microRNAs (miRNAs) and long noncoding RNA (lncRNA) as well as on ALS-related RNA binding proteins. We also review biomarkers and potential therapeutic strategies based on the manipulation of noncoding RNAs.
2. Dysfunctions in RNA metabolism and RNA-binding protein
It is broadly recognized that an aberrant RNA metabolism may contribute to RNA toxicity, which is due to the accumulation of toxic RNAs and to the dysfunction of RBPs [6].
Messenger RNAs (mRNAs) are subjected to several processing steps including splicing, polyadenylation, editing, transport, translation, and turnover. All these processes are extremely dynamic and require the involvement of RBPs to coordinate both co- and posttranscriptional processing of transcripts. Understanding RBPs functions and identifying their target RNA regulatory networks are crucial to deepen the knowledge in NDs and to promptly develop new therapeutics.
Nussbacher and colleagues by a genome-wide approach, have shed a new light on how RBPs may affect the fate of their targets [7]. Considering the great impact of RBPs on the expression, splicing, and translation of multiple RNA targets, also little changes in their expression and/or activity have amplified effects. Moreover, an altered interaction between RBPs and their targets can induce serious pathological phenotypes, even if the exact mechanism is not clear. Briefly, we focus on RBPs, TARDBP and FUS, and SOD1 and C9orf72 to highlight recent progresses on their involvement in RNA dysregulation.
In 2011, the large GGGGCC hexanucleotide repeat expansion of
3. Dysfunctions in RNA metabolism and miRNA
miRNAs are short noncoding RNAs, approximately 18–25 nucleotides long, that play a key role in the regulation of gene expression in many fundamental cellular processes and, posttranscriptionally, at the translation levels of target mRNA transcripts [44, 45]. A high number of protein-coding genes have been demonstrated to be regulated by miRNA through base-pairing interactions within the UTR of the targeted mRNAs [46, 47]. Alongside their gene silencing functions, miRNAs can also induce upregulation of their targets [48]. An accurate regulatory pathway is fundamental to control and maintain the physiological processes of cells. However, when abnormalities occur, as in diseases, a complex dysregulation of the miRNA expression takes place. In this paragraph, we will focus on miRNAs which are linked to the development of ALS and miRNA with a potential role as biomarkers.
One of the most interesting miRNAs involved in ALS is
Morlando and co-authors reported that, upon FUS depletion, the expression of
Taken together, these studies significantly contribute to evidence the importance of miRNAs, also as biomarkers for ALS. Despite these evidences, several issues need to be addressed mainly on the utility of miRNAs to serve as accurate and fast biomarkers for an early ALS diagnosis.
4. Dysfunctions in RNA metabolism and lncRNA
Long noncoding RNAs (lncRNAs) are transcripts, greater than 200 nucleotides in length, with no protein-coding potential which are found in sense or antisense orientation to protein-coding genes or within intergenic regions. lncRNAs control the gene expression through different mechanisms, that is, epigenetic modulation through chromatin remodeling, activation or repression of transcription, posttranscriptional modifications of mRNA, and regulation of protein activity by acting as scaffold to recruit RBPs and/or drive RBPs to DNA. Moreover, they can compete for and disrupt protein-binding interactions or sponge miRNAs away from their mRNA targets [68]. Recently, lncRNAs have been indicated to play important roles in the CNS in health and disease such as ALS. Nishimoto and colleagues first identify a relation between
Together with the lncRNA an increasing interest was addressed to the antisense (AS) noncoding transcripts. They are generated from the strand opposite the sense strand [74]. AS lncRNAs act by regulating chromatin, by controlling DNA methylation and/or histones modification, or by removing repressors. They promote sense transcription by recruiting transcription factors, they also regulate the half-life of their sense partners, and, in turn, they regulate gene expression [74]. About 70% of the human genome creates antisense transcripts with a great physiological and pathological significance. Ataxin 2 (ATXN2) is a coding gene related to ALS because of the association between the length of ATXN2 repeat expansion and the disease risk of ALS [75]. In 2016, Li and co-authors described the
Thanks to the deep sequencing technologies which allow high-throughput massive RNA sequencing, a wide characterization of the transcriptome profile of cell populations and tissues is now available. Three different massive transcriptome profiles have been published in different tissues (spinal cord, monocytes, and peripheral blood mononuclear cells) of ALS patients, and matched controls reported a deregulation in expressed genes [78, 79] and in lncRNAs [80]. Differences in transcriptome profiles (coding and lncRNAs) were observed in PBMCs of unmutated sALS patients, SOD1, TARDBP, and FUS mutated ALS patients and healthy controls [80]. Specifically, the authors reported a remarkable AS deregulation of genes involved in the transcription regulation pathway such as
5. Therapeutics
In the era of noncoding RNA, understanding the involvement of dysregulated miRNAs and of their targets in ALS disease is crucial to identify new pathways contributing to neurodegeneration that also offer novel opportunities for targeted intervention. miRNA-based therapeutics take advantages of two different approaches. The first involves the use of an anti-miRNA, that is, chemically modified antisense RNA, to decrease miRNA. Thus, miRNA duplex is not active and counteracts the negative regulatory effects of miRNA. This approach was first used to deliver the anti-miR-155 to the SOD1G93A transgenic mice via ventricular osmotic pumps; after this treatment the mortality was successfully delayed [59]. The second therapeutic approach using miRNA involves miRNA mimics, that is, small RNA molecules resembling miRNA precursors, that are reintroduced into cells exhibiting downregulation thus re-starting the key-related pathways [87]. Biomedical and nanoparticle engineering has begun to develop tools allowing for this specific targeting. These second-generation miRNA-based therapeutics offer the potential for a greater delivery cargo to the tissue site while reducing RNA-mediated toxicity. Overall, the continued development of innovative RNA modifications and delivery items such as nanoparticles will aid in the development of future RNA-based therapeutics for a broader range of chronic disease.
Deregulated AS is considered an important area for therapeutic intervention. Particularly, gene therapy is an encouraging pharmacological approach for patients with diseases of genetic origins. This therapy is principally based on antisense oligonucleotides (ASOs), spliceosome-mediated RNA trans-splicing (SMaRT), or small interfering RNAs (siRNAs) [88]. ASOs, that is, synthetic single-stranded nucleic acids, bind the pre-mRNA intron/exon junctions and control the splicing through their action on enhancers or repressor sequences, thus determining the skipping of the exon or including alternatively spliced exons [89].
In ALS, one of the first ASO-based clinical trials was designed to silence SOD1. The intrathecal administration of this ASO pass with good results the phase I testing. Now a phase Ib/IIa trial is in process to assess safety, tolerability, and pharmacokinetics [90].
Among the ALS-related genes, C9orf72 is one of the best candidates for ASOs therapy. Early testing of ASO-based therapeutics for C9orf72 was performed on iPSC-derived neurons and fibroblasts [91]. Specifically, ASOs were designed to target the repeat expansion or within N-terminal regions of the mRNA transcript to destroy the transcript or to prevent the interaction between the repeat expansion and the RBPs, determining a decrease in RNA foci and dipeptide proteins and recovering the normal gene expression [91]. Other studies investigated the effects of ASO on the oligonucleotide backbone, sugar, and heterocycles to promote delivery, potency, and stability to target FUS. These studies evidenced that the affinities of nucleic acid binding domains depend on chemical changes and that the interaction between ASO and protein affects the localization of ASOs themselves [92]. These data strongly indicate that ASO-based therapy could be central in treating ALS-related genes, although there is great attention on the relation between the therapeutic outcomes and the stage of disease progression and on the time of intervention.
Also many novel lncRNAs have been discovered, and the potential to become therapeutic targets is gradually increasing. Considering that lncRNAs function as decoys, regulators of translation, and scaffolds directing chromatin-modifying enzymes to specific genomic loci, they are an attractive class of therapeutic targets. The relation between HOTAIR in breast cancer [93] and MALAT1 in metastatic lung cancer [94] is a remarkable example of this association. Therefore, there is enthusiasm about the possibility to develop therapeutic tools to modulate mis-regulated lncRNAs in diseases. Although lncRNAs represent appealing pharmacological and therapeutic targets, inhibiting lncRNAs in vivo remains a challenge. A possible approach could be the use of small molecules that disrupt the complex lncRNA-chromatin that alter the epigenetic state of the target cells. All these delivery efforts, along with further elucidation of lncRNA regulatory mechanisms, will ultimately lead to the development of effective therapeutic strategies that target lncRNAs in vivo.
6. Conclusion
The impairment in RNA regulation and processing is crucial in ALS pathogenesis. Defects at different steps of RNA processing alter both cellular function and survival; thus RNA metabolism can be an essential target for therapeutic intervention for ALS and for other NDs. The application of RNA-based therapies to modulate gene and protein expression is an interesting therapeutic strategy: the preclinical application of RNA-based therapies targeting SOD1 and C9orf72 mutations are promising and pave the way to apply similar approaches for FUS and TDP-43 mutations. In conclusion, RNA-based therapies could be recommended for the future treatment of ALS.
Funding
Authors acknowledge the economic support of the Fondazione Regionale per la Ricerca Biomedica (FRRB): TRANS_ALS [2015-0023]; Finanziamento 5x1000 2016; Italian Ministry of Health GR-2016-02361552.
Abbreviations
ABLIM1 | actin-binding LIM |
ADORA2A | adenosine A2a receptor |
ALS | amyotrophic lateral sclerosis |
ANG | angiogenin |
ANXA11 | annexin A11 |
AS | antisense |
ASOs | antisense oligonucleotides |
ATG10 | autophagy related 10 |
ATXN2 | ataxin 2 |
C9ORF72 | chromosome 9 open reading frame 72 |
CCND1 | cyclin D1 |
CHCHD10 | coiled-coil-helix-coiled-coil-helix domain containing 10 |
CHMP2B | charged multivesicular body protein 2B |
CNS | central nervous system |
CSF | cerebrospinal fluid |
EWSR1 | EWS RNA binding protein 1 |
fALS | familial amyotrophic lateral sclerosis |
FTLD | frontotemporal lobar degeneration |
FUS | fused in sarcoma/translocated in liposarcoma |
GABRA2 | gamma-aminobutyric acid type A receptor alpha2 subunit |
GABRA3 | gamma-aminobutyric acid type A receptor alpha3 subunit |
GRIA3 | glutamate ionotropic receptor AMPA type subunit 3AMPA receptor subunits |
GRIA4 | glutamate ionotropic receptor AMPA type subunit 4AMPA receptor subunits |
HNRNPA1 | heterogeneous nuclear ribonucleoprotein A1 |
HNRNPA2/B1 | heterogeneous nuclear ribonucleoprotein A2/B1 |
Homer2 | homer scaffold protein 2 |
HOTAIR | HOX transcript antisense RNA |
HuR | Hu antigen R |
iPSC | induced pluripotent stem cell |
KIF5A | kinesin family member 5A |
lncRNA | long noncoding RNA |
lncRNAs | long noncoding RNAs |
MALAT1 | metastasis-associated lung adenocarcinoma transcript 1 |
MAP1B | microtubule-associated protein 1B |
MAPT | microtubule-associated protein tau |
MATR3 | matrin 3 |
miRNAs | microRNAs |
MN | motor neuron |
ND | neurodegenerative disorder |
NEAT1 | nuclear-enriched autosomal transcript 1 |
NES | nuclear export signals |
NF-kB | nuclear factor kappa B subunit 1 |
NFL | neurofilament light chain |
NLGN1-2 | neuroligin |
NLS | nuclear localization |
NONO | non-POU domain-containing octamer-binding protein |
NRCAM | neuronal cell adhesion molecule |
NRXN1-3 | neurexin |
NTNG1 | netrin G1 |
OPTN | optineurin |
PFN1 | profilin 1 |
PTX3 | pentraxin 3 |
RBP | RNA-binding proteins |
RRM1-2 | RNA recognition motifs 1-2 |
RUNX | Runbox transcription factor |
sALS | sporadic amyotrophic lateral sclerosis |
siRNAs | small interfering RNAs |
SMaRT | spliceosome-mediated RNA trans-splicing |
SOD1 | superoxide dismutase 1 |
SPI1 | Spi-1 proto-oncogene |
SQSTM1 | sequestosome 1 |
SYGQ | N-terminal serine-tyrosine-glycine-glutamine |
TAF15 | TATA-box binding protein-associated factor 15 |
TARDBP | TAR DNA-binding protein |
TBK1 | TANK-binding kinase 1 |
TGF-β1 | transforming growth factor-beta |
TIAR | TIA1 cytotoxic granule-associated RNA binding protein like 1 |
TUBA4A | tubulin alpha 4a |
UBQLN2 | ubiquilin 1 |
UBXN7 | UBX domain protein 7 |
UTR | 3′-untranslated |
VAPB | vesicle-associated membrane protein-associated protein B/C |
VCP | valosin-containing protein |
VEGF | vascular endothelial growth factor |
ZBTB11 | zinc finger and BTB domain-containing 11 |
ZEB1 | zinc finger E-box-binding homeobox 1 |
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