review review Figure 1. Microsatellite susceptible genes are featured by bidirectional transcription. (A and B) Fragile X Syndrome. (A) in general population the gene FMR1 contains at the 5’ UTr up to 54 CGG repeat that do not interfere with the expression of the gene. in this locus, in people not affected by Fragile X syndrome, antisense noncoding r NAs have been reported to be transcribed from intron 2 (AS-FMR1) and from the promoter (FMR4). (B) Amplification of CGG trinucleotides over 200 is as- sociated with the onset of X-linked mental retardation and it’s coupled with cytosine methylation that results in transcriptional silencing of the protein-coding gene FMr 1 and the non-protein coding AS-FMR1 and FMR4. (C and D) Spinocerebellar Ataxia type 7. Spinocerebellar Ataxia 7 is caused by a CAG repeats expansion (37–400) located in proximity of the translation start site of Ataxin-7 protein leading to polyglutamine (polyQ) accumulation (C). Ataxin-7 gene is featured by CAG repeats flanked by CTCF-binding sites and by an alternative TSS of the antisense r SCAANT1 (Spinocerebellar ataxia-7 antisense noncoding transcript 1) (D). in patients affected by Ataxia-7 the expansion of trinucleotides af- fects the binding of CTCF that causes reduced transcription of SCAANT1 and results in higher expression of the aberrant Ataxin-7 protein (C). (e) SpinocerebellarAtxia type 8. Spinocerebellar Ataxia type 8 arises when trinucleotide CTG in the ATXN8 gene expand over 70 repeats (70–250). Bidirectional transcription has been detected in ATNX8 gene producing protein coding gene ATXN8 and the non-proteincoding r ATXN8OS. CTG repeats in ATNX8 mr results in accumulation of polyQ proteins while CTG repeats transcribed in antisense direction (CAG) are not translated and result in the production of toxic noncoding r NAs. affects the basic functions of neuronal cells resulting in neuro- logical and psychiatric disorders.31-33 In addition, hundreds of small non-coding RNA molecules have been identified in the mammalian central nervous system. Among these are microRNAs (miRNAs) which have dem- onstrated importance in many aspects of neuronal function. Disruption of gene regulation mediated by miRNA has been implicated in a range of disorders such as neurodegenerative and neuropsychiatric conditions as well as in tumors of the CNS. The focus of this review is to highlight the possible roles of the less explored long-noncoding RNAs in diseases of the CNS. For a comprehensive review of microRNA and other small RNA impli- cated in brain development and dysfunctions we refer the reader to other publications.34-37 LncRNAs in microsatellite expansion diseases. Microsatellite expansion (or trinucleotide repeats) give rise to more than 30 neurological and neuromuscular diseases, including: Huntington disease (HD), Fragile X syndrome (FXS) and Spinocerebellar Ataxias.38,39 Transcriptomics efforts have revealed that anti- sense transcription is a common feature of mammalian genes that are actively transcribed from microsatellite disease loci.9,40,41 Transcription of lncRNAs containing repeats might alter their function and interfere with their ability to recruit protein com- plexes. The presence of nucleotide repeats might also alter the basal expression of lncRNAs, leading to an imbalance in sense- antisense transcript levels. Here, we highlight some of the recent findings showing that altered expression of specific lncRNAs might be involved in the etiology of several neurological disorders. Fragile X syndrome. Fragile X syndrome (FXS) is the most common human heritable mental disorder. Patients display autis- tic symptoms and often suffer from epilepsy. A triplet nucleo- tide repeat expansion (> 200 repeats) in the 5' UTR of FMR1, the gene that encodes the crucial neuronal development protein, FMRP, is the causal factor in FXS (Fig. 1A and B). This repeat expansion results in the methylation of the promoter and subse- quent silencing of the FMR1 gene. Recent studies have suggested that noncoding RNAs may play a role in FXS as several lncRNAs are generated from the FMR1 gene locus.9,10 The long antisense RNA originating from intron 2, ASFMR1, has multiple alterna- tive splicing patterns and spans the long repeat sequence end- ing in the gene promoter.9 Another natural antisense transcript, FMR4, (~2 kb long, unspliced transcript) is initiated upstream of the FMR1 start site.10 Previously, we have described that FMR4 plays a role in cell survival as FMR4 overexpression increases cell proliferation while FMR4 downregulation induces apoptosis.10 We did not observe a cis acting effect on the expression of the FMR1 gene and thus hypothesized that the ability of FMR4 to interfere with proliferation pathways might occur in trans, how- ever this has not yet been clarified. Moreover, FMR4, like FMR1, is silenced in Fragile X patients, thus its absence in the neurons of affected patients might contribute to the pathogenesis of this neurological disorder. Spinocerebellar ataxias. Spinocerebellar ataxias are a diverse group of rare, slowly progressing, neurological disorders affect- ing the cerebellum. Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder caused by CAG repeat tract (37 ≥ 400 repeats) in the ataxin-7 gene as compared with nor- mal individuals (4–35 repeats).42,43 The expansion region is flanked by binding sites for the transcription factor CTCF44 and by the TSS of the antisense transcript SCA ANT1 (spino- cerebellar ataxia 7 antisense noncoding transcript 1) 44 (Fig. 1C and D). Evidence for CTCF binding in close proximity to the repeat sequences is emerging as a common occurrence in microsatellite expansion diseases. Importantly, CTCF binding is required for SCA ANT1 transcription and it has been shown www.landesbioscience.com rNA Biology 861