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. 2013 Dec 30;6:53.
doi: 10.3389/fnmol.2013.00053.

Long Non-Coding RNAs in Neurodevelopmental Disorders

Free PMC article

Long Non-Coding RNAs in Neurodevelopmental Disorders

Ilse I G M van de Vondervoort et al. Front Mol Neurosci. .
Free PMC article


Recent studies have emphasized an important role for long non-coding RNAs (lncRNA) in epigenetic regulation, development, and disease. Despite growing interest in lncRNAs, the mechanisms by which lncRNAs control cellular processes are still elusive. Improved understanding of these mechanisms is critical, because the majority of the mammalian genome is transcribed, in most cases resulting in non-coding RNA products. Recent studies have suggested the involvement of lncRNA in neurobehavioral and neurodevelopmental disorders, highlighting the functional importance of this subclass of brain-enriched RNAs. Impaired expression of lnRNAs has been implicated in several forms of intellectual disability disorders. However, the role of this family of RNAs in cognitive function is largely unknown. Here we provide an overview of recently identified mechanisms of neuronal development involving lncRNAs, and the consequences of lncRNA deregulation for neurodevelopmental disorders.

Keywords: autism spectrum disorders; fragile X syndrome; genomic imprinting; intellectual disability; long non-coding RNA; nervous system development; schizophrenia.


An overview of known regulatory mechanisms for lncRNA. Transcription from an upstream promoter can negatively or positively affect the expression of a downstream gene via (1) transcriptional interference mediated by inhibition of RNA Polymerase 2 recruitment, or by (2) inducing chromatin remodeling and histone modification. Alternatively, an antisense transcript is able to hybridize to the overlapping sense transcript and modulate further processing (3), or provide a substrate for Dicer, or other nucleases, in order to generate various small non-coding RNAs (4). By binding to specific protein partners, a long noncoding transcript may modulate the activity of that particular protein (5), serve as a structural component that allows the formation of a larger RNA–protein complex (6), or alter the cellular localization of the protein (7).
Proposed strategy for a therapeutic application of Xist and zinc finger nucleases (ZFN) to treat trisomy 21. Adeno-associated viruses (AAVs) are currently the most promising CNS gene delivery vector (for review, see Gray, 2013). As shown in this scheme, the first step in the approach would be incorporation of plasmids containing Xist and ZFN targeted to the DYRK1A locus on chromosome 21 in AAVs (1). Next, injection of the viruses in rodents can be performed intracranial, intravenous or in the cerebrospinal fluid (2). Intracranial injections have been successfully performed in mammals as large as cats, but an estimated number of 20–30 required injections per hemisphere in human infants rendered this technique unfavorable over alternatives (Vite et al., 2005). AAV9 vectors have the capacity to cross the blood-brain barrier and transduce neurons and astrocytes (Foust et al., 2009), making intravascular injection of viral vectors for CNS targeted gene therapy a possibility. The third possible route of administration is injecting the viral vectors in the cerebrospinal fluid (CSF), thus transducing the central nervous system effectively even in non-human primates (Samaranch et al., 2012). After injection of the AAVs and transduction of the viruses in the cells, Xist will be incorporated on the ZFN target site in the DYRK1A locus on chromosome 21 (3). Here, it will induce the formation of a chromosome 21 Barr body (4), which will lead to gene silencing and hypermethylation of promoter CPG islands, effectively stabilizing the inactivation of the chromosome (5; Jiang et al., 2013). Eventually, this approach may lead to a CNS-wide inactivation of the third chromosome 21, thereby reducing the symptoms of the trisomy 21 disorder. However, several major limitations have to be overcome in order to translate this proposed approach to humans. First, the optimal age for the therapeutic intervention should be established. The majority of the in vivo gene therapy studies have been performed in juvenile or adult animals, but starting the treatment at an earlier age should be considered in order to achieve the best therapeutic effect. Moreover, the optimal route of delivery for CNS gene therapy is currently not established yet, with possibilities being intravascular injection, injection in the CSF, and to a lesser extend, intracranial injections. Third, a practical issue of using AAVs in the therapeutic approach is the limitation of AAVs to contain vectors up to only 4.7 kb in length. This is insufficient for the Xist containing vector used in the proof-of-principle study by Jiang et al. (2013). Last, comparing intravascular injection of vectors with a CNS target revealed that both neuronal and overall transduction efficiency in primates is considerably lower than in rodents, the latter most likely due to circulating pre-existing neutralizing AAV antibodies (Gray et al., 2011).

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