that the knockdown of SCAANT1 or the absence of CTCF increases ataxin-7 sense gene transcription. Based on this evi- dence, we can speculate that the overexpression of the antisense SCAANT1 could be attempted to silence the aberrant expres- sion of Ataxin-7. CTCF and lncRNA-mediated regulation of genomic architecture could play crucial roles in transcriptional deregulation at repeat loci. Interestingly, CTCF binding sites have also been detected in the promoter region of FMR1,9,45 suggesting that CTCF might regulate FMR1 and FMR1 locus- related noncoding RNA transcription or regional chromatin loop formation.46 Spinocerebellar ataxia type 8 (SCA8) is characterized by a nucleotide repeat expansion in a region containing two transcripts expressed in opposite directions. Nucleotide repeat involves both the ATXN8 protein coding gene and the ATXN8OS antisense noncoding gene.40 Transcription of ATXN8 protein-coding RNA containing CAG repeats is translated into a polyglutamine expan- sion protein while the untranslated antisense partner expresses CUG repeats (Fig. 1E). These findings suggest that SCA8 patho- genesis involves a toxic gain of function at both the RNA and protein levels. In fact, polyglutamine protein (PolyQ) inclusions have been found in SCA8 human tissues40 and CUG expansions in the antisense transcript accumulate as ribonuclear inclusions in GABAergic neurons.47 Despite the known role of the antisense transcripts in causing RNA toxicity, the authors speculate on the possibility that the noncoding transcripts might have additional roles in Spinocerebellar ataxia 8 that eventually regulate sense transcript expression.48 In summary, it is becoming clear that repeat expansion dis- eases feature: (1) genetic instability and a strong tendency for repeat expansion through generations,49 (2) binding sites for CTCF50 and (3) bidirectional transcription encompassing the repeats.51 Huntington’s disease. Investigation of potentially important accelerators of evolution have focused primarily on protein cod- ing genes.52,53 However the availability of nearly complete genome sequences for several vertebrates provides useful information to find functional elements in the roughly 99% of the genome that does not have protein coding capacity.54,55 Many human acceler- ated regions (HARs) are associated with genes involved in tran- scriptional regulation and neurodevelopment. The HAR1 region contains long noncoding RNAs (HAR1F and HAR1R) and is expressed early during human embryonic neocortical develop- ment.27 HAR1F is specifically expressed in Cajal-Retzius neurons in the marginal zone during early development of the cortex and becomes expressed later on in other regions, e.g., in the hippo- campal primordium, dentate gyrus, cerebellar cortex and olivar complex.27 In the adult brain, HAR1F is expressed in the frontal cortex, hippocampus, cerebellum, thalamus and hypothalamus.27 Recently, it has been shown that in the brain of patients affected by Huntington’s disease (HD), a trinucleotide expansion disease, the levels of lncRNAs HAR1F and HAR1R are decreased as com- pared with normal brains, suggesting a putative functional role for these lncRNAs in this disease. At the molecular level, the neu- rons of Huntington’s disease patients are disrupted by aberrant nuclear localization of the master transcriptional repressor REST (RE1-silencing transcription factor).56 Furthermore, ChIP-seq data has revealed that the HAR1 locus is under the control of REST57 and that in the brain of HD HAR1-associated lncRNAs are part of widespread transcriptional dysfunction. Long noncoding RNAs in imprinting-related diseases. Long noncoding RNAs have been implicated in the phenomenon of gene imprinting, where genes for only one allele (maternal or paternal) are actively transcribed. Imprinted genes are enriched in the brain and placenta and help mediate various cellular processes including cell growth and development.58,59 There is increasing evidence that imprinted genes are linked to neurodevelopmen- tal processes through the regulation of cell survival, differentia- tion and maturation.59,60 Mental and neurological disorders are often influenced by deregulation of the imprinting processes. For example, genomic imprinting has been implicated in bipolar disorder, schizophrenia and autism.61-63 Interestingly, imprinted genes are frequently associated with antisense transcripts,64 which might play a role in gene silencing and could be causal factor in neurological disorders.3,4 Angelman syndrome. Imprinted genes play a role in several human congenital syndromes such as Angelman syndrome (AS),65 a disease characterized by severe neurologic abnormali- ties. The gene involved in this disorder, Ube3a, is biallelically expressed in most of the body’s tissues, however in the brain, neurons express Ube3a only from the maternal allele.66 Notably, in Angelman sufferers, the maternal Ube3a gene is deleted or mutated66-68 resulting in the absence of Ube3a expression in neu- rons. Currently, there are no effective drugs to treat this disorder, however activation of the dormant paternal allele has recently been achieved through treatment with topoisomerase inhibitors.69 The activation of the silenced paternal allele is linked to a decrease in expression of the paternally expressed antisense transcript in neurons.69 The mechanism behind this phenomenon remains unclear as the link between topoisomerase treatment, repres- sion of the antisense transcript and re-expression of the gene is still obscure. These findings suggest that the re-expression of the paternal allele driven by a topoisomerase inhibitor, Topotecan, might be a potential treatment for Angelman syndrome. Long noncoding RNAs and neuronal degeneration. Alzheimer disease. Long ncRNAs are involved in the pathogen- esis of Alzheimer disease (AD),14,70 a neurodegenerative disorder partly characterized histologically by the deposition of amyloid plaques in the brain, due to increased levels of the β-secretase enzyme (BACE1). BACE1 cleaves the amyloid precursor pro- tein (APP) and generates amyloid peptides which can aggregate and form plaques. A conserved antisense RNA, BACE1-AS, was originally identified from data produced by large-scale transcrip- tomics efforts from the FANTOM consortium as one of the sense-antisense pairs conserved between human and mouse.71 BACE1-AS is an approximately 2 kb RNA that is transcribed on chromosome 11, from the opposite strand of the BACE1 locus (11q 23.3). BACE1-AS shares 104 nucleotides of full complemen- tarity to exon 6 of human BACE1 mRNA. It has been shown that BACE1-AS and BACE1 mRNA form a duplex that may act to alter the secondary or tertiary structure of BACE1 and to increase BACE1 mRNA stability.14 Alzheimer disease patients 862 rNA Biology volume 9 issue 6