期刊
NEUROBIOLOGY OF DISEASE
卷 41, 期 2, 页码 308-317出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2010.09.019
关键词
RNA polymerase III; Neurodegeneration; Inflammation; Amyloid beta
资金
- Italian Ministry of University
- MIUR
- Associazione Italiana per la Ricerca sul Cancro (AIRC) [IG 9378, IG 9889]
- Italian Ministry of University and Research
- AICCRE-Regione Emilia Romagna
Alternative splicing is a central component of human brain complexity: nonetheless, its regulatory mechanisms are still largely unclear. In this work, we describe a novel non-coding (nc) RNA (named 17A) RNA polymerase (pol) III-dependent embedded in the human G-protein-coupled receptor 51 gene (GPR51, GABA B2 receptor). The stable expression of 17A in SHSY5Y neuroblastoma cells induces the synthesis of an alternative splicing isoform that abolish GABA B2 intracellular signaling (i.e., inhibition of cAMP accumulation and activation of K+ channels). Indeed, 17A is expressed in human brain, and we report that it is upregulated in cerebral tissues derived from Alzheimer disease patients. We demonstrate that 17A expression in neuroblastoma cells enhances the secretion of amyloid beta peptide (A beta) and the A beta x-42/A beta x-40 peptide ratio and that its synthesis is induced in response to inflammatory stimuli. These data correlate, for the first time, the activity of a novel pol III-dependent ncRNA to alternative splicing events and, possibly, to neurodegeneration induced by abnormal GABA B function. We anticipate that further analysis of pol III-dependent regulation of alternative splicing will disclose novel regulatory pathways associated to brain physiology and/or pathology. (C) 2010 Elsevier Inc. All rights reserved.
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