Background: Amyotrophic lateral sclerosis (ALS) is a fatal disorder caused by the progressive degeneration of motoneurons in brain and spinal cord. Despite identification of disease-linked mutations, the diversity of processes involved and the ambiguity of their relative importance in ALS pathogenesis still represent a major impediment to disease models as a basis for effective therapies. Moreover, the human motor cortex, although critical to ALS pathology and physiologically altered in most forms of the disease, has not been screened systematically for therapeutic targets.
Apoptosis, the main form of programmed cell death, is associated to a complex and dynamic transcriptional and post-transcriptional programme. By microarray analysis, we have previously implicated 241 genes differentially expressed in rat cortical neurons exposed to beta-amyloid (Abeta) protein, the major constituent of amyloid plaques in Alzheimer's disease. A large number of identified genes have no name or known function. In the present study, we have investigated one of these genes that encodes for a natural antisense transcript against Rad18 (NAT-Rad18). Real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) confirmed differential expression of this transcript in cortical neurons exposed to Abeta. In situ hybridization, qRT-PCR and immunohistochemistry were used to assess the regional and cellular distribution of NAT-Rad18 in adult rat brain. These experiments showed a widespread distribution of NAT-Rad18, with the highest levels in the cerebellum, brainstem and cortex, where it was specifically expressed by neurons. NAT-Rad18 was also strongly expressed in epithelial cells of choroid plexus and cerebral vessels. At the cellular level, expression of Rad18 was counterbalanced by that of its natural antisense transcript, as shown by both in situ hybridization and immunohistochemistry. These experiments suggest the existence of a NAT that exerts a post-transcriptional control over Rad18.
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