title: An intronic ncRNA-dependent regulation of SORL1 expression affecting Aβ formation is upregulated in post-mortem Alzheimer's disease brain samples.
abstract: Recent studies indicated that sortilin-related receptor 1 (SORL1) is a risk gene for late-onset Alzheimer's disease (AD), although its role in the aetiology and/or progression of this disorder is not fully understood. Here, we report the finding of a non-coding (nc) RNA (hereafter referred to as 51A) that maps in antisense configuration to intron 1 of the SORL1 gene. 51A expression drives a splicing shift of SORL1 from the synthesis of the canonical long protein variant A to an alternatively spliced protein form. This process, resulting in a decreased synthesis of SORL1 variant A, is associated with impaired processing of amyloid precursor protein (APP), leading to increased Aβ formation. Interestingly, we found that 51A is expressed in human brains, being frequently upregulated in cerebral cortices from individuals with Alzheimer's disease. Altogether, these findings document a novel ncRNA-dependent regulatory pathway that might have relevant implications in neurodegeneration.
authors.affiliation: Department of Experimental Medicine, University of Genoa, Genoa 16132, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Ciarlo
authors.forename: Sara
authors.initials: S
authors.lastname: Massone
authors.forename: Ilaria
authors.initials: I
authors.lastname: Penna
authors.forename: Mario
authors.initials: M
authors.lastname: Nizzari
authors.forename: Arianna
authors.initials: A
authors.lastname: Gigoni
authors.forename: Giorgio
authors.initials: G
authors.lastname: Dieci
authors.forename: Claudio
authors.initials: C
authors.lastname: Russo
authors.forename: Tullio
authors.initials: T
authors.lastname: Florio
authors.forename: Ranieri
authors.initials: R
authors.lastname: Cancedda
authors.forename: Aldo
authors.initials: A
authors.lastname: Pagano
mesh_terms: D000368:Aged; D017398:Alternative Splicing / Q000235:genetics; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001483:Base Sequence; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002457:Cell Extracts; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D005260:Female; D006801:Humans; D007438:Introns / Q000235:genetics*; D026502:LDL-Receptor Related Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D011180:Postmortem Changes; D022661:RNA, Untranslated / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000235:genetics*
chemical_list: D016229:Amyloid beta-Peptides; D002457:Cell Extracts; D026502:LDL-Receptor Related Proteins; D026901:Membrane Transport Proteins; D022661:RNA, Untranslated; C102582:SORL1 protein, human