Figure 2. BACe1-AS contributes to β-secretase increased production in the brain of Alzheimer disease patients. Alzheimer disease associates with amyloid plaques in the brain of affected patients. The generation of these plaques derives by sequential cleavage of the amyloid precursor protein (APP) by β-secretase (BACe1) and β-secretase. BACe1 is increased in affected patients due to the stabilization of the mr caused by the binding to its antisense noncoding r (BACe1-AS). Oxidative stress has been reported to cause the increase of BACe-AS in brain resulting in the increased produc- tion of β-secretase enzyme. display elevated levels of BACE1-AS in several brain regions as compared with controls.14 Furthermore, BACE1-AS increases sig- nificantly upon cellular stress causing an upregulation in BACE1 mRNA and protein levels (Fig. 2). These findings are particu- larly interesting from a therapeutic standpoint as BACE1 remains a viable target for AD treatment. Long noncoding RNAs in neurologic and neuropsychiat- ric diseases. Certain lncRNAs have been mapped to chromo- somal regions associated with neurobehavioral diseases such as schizophrenia and autism.72 Many schizophrenic patients carry a translocation affecting two genes: DISC1 and DISC2 (disrupted in schizophrenia 1 and 2).73 The DISC1 protein is involved in intracellular transport, cell polarity and neuronal migration and disruption of its function may in part contribute to some neuro- logical defects.28 DISC2 produces antisense non-protein coding transcripts that are transcribed from the 3' region of protein- coding DISC1. It has been proposed that DISC2 ncRNA may be involved in the regulation of DISC1 expression.73 Interestingly, it has also been suggested that the DISC1 and DISC2 genes might also play a role in the development of unipolar and bipo- lar depressive disorders.74 The same chromosomal translocation also disrupts another ncRNA gene, PSZA11q14 (putative schizo- phrenia-associated gene from 11q14), which is downregulated in schizophrenia patients.75 It is well recognized that neuropsychi- atric conditions such as schizophrenia, depression and bipolar disorder are severe, multifactorial brain illnesses, thus it is not surprising that previously unrecognized noncoding RNAs can affect multiple pathways at different levels in these diseases. The long ncRNA Evf-2 is transcribed from the Dlx5/6 locus and its transcription regulates that of Dlx5, Dlx6 and Gad1 16,76 through the recruitment of transcription factors such as MeCP2. In vertebrates, Dlx genes play a critical role in neuronal develop- ment16 and the loss of Evf2 noncoding RNA results in a decreased number of GABAergic interneurons in the early postnatal mouse hippocampus and dentate gyrus.76 Schizophrenic patients show a consistent reduction of the enzyme responsible for GABA syn- thesis and the dysfunction of GABA-regulated circuits have been implicated in other neurological disorders such as autism and epi- lepsy.77 Thus, the discovery that Evf2 controls the development of GABAergic interneurons76 raises the possibility of targeting this pathway to attenuate specific disease-associated symptoms. Long noncoding RNAs in brain tumors. Gliomas. Gliomas are brain tumors that originate from glial cells (astrocytes, oli- godendrocytes or ependymal cells). Among these, astrocytoma grade IV (glioblastoma multiforme, GBM), is the most common malignant brain tumor in adults and is one of the deadliest can- cers. Despite the development of new surgical techniques and the use of antineoplastic drugs combined with irradiation, a cure for glioblastoma does not yet exist. Glioblastomas are a heterogeneus group of cancers that show a number of clearly defined genetic lesions. For instance, in younger patients this tumor frequently features p53 mutations. p53 is a tumor suppressor protein encoded by a gene whose disruption is associated with more than 50% percent of human cancers. The p53 protein is known as the guardian of the genome because it acts as a checkpoint in the cell cycle that either prevents or ini- tiates programmed cell death. Recent studies identified numer- ous long intergenic RNAs (lincRNAs) that are induced by the p53 tumor-suppressor pathway.11,78 When cells are subjected to stress, lincRNAs are among the transcripts specifically induced by p53. In particular, lincRNA-p21, is directly induced by p53 www.landesbioscience.com rNA Biology 863