An intronic ncRNA-dependent regulation of SORL1 expression affecting Aβ formation is upregulated in post-mortem Alzheimer's disease brain samples

Abstract

SUMMARYRecent 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.

The Long Non-Coding RNAs in Neurodegenerative Diseases: Novel Mechanisms of Pathogenesis

“…Similarly, the up-regulation of the lncRNA NDM29 promoted Aβ secretion with an unbalance in the Aβ42/Αβ40 peptide ratio ( Figure 2) [61]. Also the antisense ncRNA 51A, deriving from the first intron of SORL1 gene, a well recognized risk factor for AD, was described to promote the alternative splicing of SORL1 and to increase Aβ formation [62]. Interestingly, both 17A and NDM29 ncRNA expression can be induced by inflammatory stimuli, which represent a pathogenic mechanism in AD, with the possibility of modulating such effect on Aβ synthesis by using anti-inflammatory drugs [60; 61].…”

“…Although the mode of action of such deregulated lncRNAs is mainly unknown so far, it will be interesting to test whether such lncRNAs may serve as disease-specific biomarkers for AD. The expression of three specific lncRNAs, 17A, NDM29 and 51A was reported to be upregulated in AD affected brains compared to healthy control brain tissues [60][61][62]. The lncnRNA 17A, embedded in an antisense orientation in the third intron of the human G-protein-coupled receptor 51 (GPR51, also known as GABBR2) gene, was demonstrated to regulate GPR51/GABBR2 pre-mRNA processing and favour the generation of the alternative and unfunctional splicing isoform B of the GABA B receptor (GABAB R2) ( Figure 2) [60].…”

Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration

“…This short sequence lacks enzymatic activity and may function as a docking domain for cytosolic as well as membrane-bound proteins (46,(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(67)(68)(69)(70)(71)(72). To explore the potential role of the ACR, we used a proteomic approach (28,48 ), and St-ACR with phosphorylation on both Thr 668 and Tyr 682 (St-ACR Thr(P)Tyr(P) ), were immobilized on StrepTactin resin.…”

Down-regulation of 21A Alu RNA as a tool to boost proliferation maintaining the tissue regeneration potential of progenitor cells

“…2 In the recent years we defined the transcriptional role of several of these ncRNA. [13][14][15][16][17][18][19] While investigating the biological role of one of these transcription units (named 21A), we documented an inverse correlation between the expression level of 21A ncRNA and the rate of cell proliferation. 2 Indeed, the transfection of cells with a construct expressing 21A ncRNA in antisense configuration led to a marked increase of cell proliferation.…”