17A, a novel non-coding RNA, regulates GABA B alternative splicing and signaling in response to inflammatory stimuli and in Alzheimer disease.
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 β peptide (Aβ) and the Aβ x-42/Αβ 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.
Massone
Sara
S
Oncology Biology and Genetics Department (DOBiG), University of Genoa, Genoa, Italy.
Vassallo
Irene
I
Fiorino
Gloria
G
Castelnuovo
Manuele
M
Barbieri
Federica
F
Borghi
Roberta
R
Tabaton
Massimo
M
Robello
Mauro
M
Gatta
Elena
E
Russo
Claudio
C
Florio
Tullio
T
Dieci
Giorgio
G
Cancedda
Ranieri
R
Pagano
Aldo
A
D017398:Alternative Splicing / Q000235:genetics*; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D001483:Base Sequence; D045744:Cell Line, Tumor; D006367:HeLa Cells; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D008969:Molecular Sequence Data; D012320:RNA Polymerase III / Q000235:genetics / Q000502:physiology; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics* / Q000494:pharmacology / Q000502:physiology; D011963:Receptors, GABA-A / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics
C567939:17A non-coding RNA, human; C495710:GABRB2 protein, human; D018836:Inflammation Mediators; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D011963:Receptors, GABA-A; D012320:RNA Polymerase III