Circular RNAs (circRNAs) are emerging as a promising object of study in Alzheimer's disease (AD) pathogenesis. Expression differences in circRNAs have been correlated with disease; however, the presence of pathogenic variants has not been observed until now. Here, we examine circRNAs derived from two AD-related genes, presenilin 1 (PSEN1) and presenilin 2 (PSEN2), in the prefrontal cortex from individuals with familial AD, identifying four variants in circRNAs derived from PSEN1 (I143T, S212Y, M146L) and PSEN2 (N141I). The discovery of pathogenic variants in PSEN1 and PSEN2 circRNAs marks a first step in determining whether they play a role in AD etiology.
SangerHLKlotzGRiesnerD, et al.Viroids are single-stranded covalently closed circular RNA molecules existing as highly base-paired rod-like structures. Proc Natl Acad Sci U S A1976; 73: 3852–3856.
2.
SalzmanJGawadCWangPL, et al.Circular RNAs are the predominant transcript isoform from hundreds of human genes in diverse cell types. PLoS One2012; 7: e30733.
3.
SalzmanJChenREOlsenMN, et al.Cell-type specific features of circular RNA expression. PLoS Genet2013; 9: e100377.
Rybak-WolfAStottmeisterCGlažarP, et al.Circular RNAs in the mammalian brain are highly abundant, conserved, and dynamically expressed. Mol Cell2015; 58: 870–885.
6.
DongXBaiYLiaoZ, et al.Circular RNAs in the human brain are tailored to neuron identity and neuropsychiatric disease. Nat Commun2023; 14: 5327.
7.
YouXVlatkovicIBabicA, et al.Neural circular RNAs are derived from synaptic genes and regulated by development and plasticity. Nat Neurosci2015; 18: 603–610.
8.
ShaoTPanYXiongX. Circular RNA: an important player with multiple facets to regulate its parental gene expression. Mol Ther Nucleic Acids2021; 23: 369–376.
9.
LukiwWJ. Circular RNA (circRNA) in Alzheimer’s disease (AD). Front Genet2013; 4: 307.
10.
ChenH-HEteleebAWangC, et al.Circular RNA detection identifies circPSEN1 alterations in brain specific to autosomal dominant Alzheimer’s disease. Acta Neuropathol Commun2022; 10: 29.
11.
CorsiGIGadekarVPHaukedalH, et al.The transcriptomic landscape of neurons carrying PSEN1 mutations reveals changes in extracellular matrix components and non-coding gene expression. Neurobiol Dis2023; 178: 105980.
12.
DubeUDel-AguilaJLLiZ, et al.An atlas of cortical circular RNA expression in Alzheimer disease brains demonstrates clinical and pathological associations. Nat Neurosci2019; 22: 1903–1912.
13.
SmukowskiSNDanykoCSombergJ, et al.mRNA and circRNA mislocalization to synapses are key features of Alzheimer’s disease. PLOS Genet2024; 20: e1011359.
14.
LoIHillJVilhjálmssonBJ, et al.Linking the association between circRNAs and Alzheimer’s disease progression by multi-tissue circular RNA characterization. RNA Biol2020; 17: 1789–1797.
15.
BirdTD. Alzheimer disease overview. In: AdamMPArdingerHHPagonRA (eds) Genereviews [internet]. Seattle, WA: University of Washington, 2018, pp.1–12.
16.
Carrillo-MoraPLunaRColín-BarenqueL. Amyloid beta: multiple mechanisms of toxicity and only some protective effects?Oxid Med Cell Longev2014; 2014: 795315–795375.
17.
JackCRKnopmanDSJagustWJ, et al.Update on hypothetical model of Alzheimer’s disease biomarkers. Lancet Neurol2013; 12: 207–216.
18.
GlažarPPapavasileiouPRajewskyN. Circbase: a database for circular RNAs. RNA2014; 20: 1666–1670.
19.
CourseMMGudsnukKKeeneCD, et al.Aberrant splicing of PSEN2, but not PSEN1, in individuals with sporadic Alzheimer’s disease. Brain2023; 146: 507–518.
DodbeleSMutluNWiluszJE. Best practices to ensure robust investigation of circular RNAs: pitfalls and tips. EMBO Rep2021; 22: e52072.
22.
BragginJEBucksSACourseMM, et al.Alternative splicing in a presenilin 2 variant associated with Alzheimer disease. Ann Clin Transl Neurol2019; 6: 762–777.
23.
ConnVConnSJ. Splintquant: a method for accurately quantifying circular RNA transcript abundance without reverse transcription bias. RNA2019; 25: 1202–1210.
24.
JaijyanDKYangSRamasamyS, et al.Imaging and quantification of human and viral circular RNAs. Nucleic Acids Res2024; 52: e70.
25.
IadecolaC. Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat Rev Neurosci2004; 5: 347–360.
26.
SatoNHoriOYamaguchiA, et al.A novel presenilin-2 splice variant in human Alzheimer’s disease brain tissue. J Neurochem1999; 72: 2498–2505.
27.
Moussavi NikSHNewmanMWilsonL, et al.Alzheimer’s disease-related peptide PS2V plays ancient, conserved roles in suppression of the unfolded protein response under hypoxia and stimulation of γ-secretase activity. Hum Mol Genet2015; 24: 3662–3678.
28.
ManabeTKatayamaTSatoN, et al.Induced HMGA1a expression causes aberrant splicing of Presenilin-2 pre-mRNA in sporadic Alzheimer’s disease. Cell Death Differ2003; 10: 698–708.
29.
Levy-LahadEWascoWPoorkajP, et al.Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science1995; 269: 973–977.
30.
RogaevEISherringtonRRogaevaEA, et al.Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature1995; 376: 775–778.
31.
JayadevSLeverenzJBSteinbartE, et al.Alzheimer’s disease phenotypes and genotypes associated with mutations in presenilin 2. Brain2010; 133: 1143–1154.
32.
LarnerAJDoranM. Genotype-phenotype relationships of presenilin-1 mutations in Alzheimer’s disease: an update. J Alzheimers Dis2009; 17: 259–265.
33.
MorandellJMonzianiALazioliM, et al.CircHTT(2,3,4,5,6)— co-evolving with the HTT CAG-repeat tract — modulates Huntington’s disease phenotypes. Mol Ther Nucleic Acids2024; 35: 102234.
34.
WhittleBJIzuoguOGLowesH, et al.Early-stage idiopathic Parkinson’s disease is associated with reduced circular RNA expression. NPJ Parkinsons Dis2024; 10: 25.
35.
CardamoneGParaboschiEMSoldàG, et al.The circular RNA landscape in multiple sclerosis: disease-specific associated variants and exon methylation shape circular RNA expression profile. Mult Scler Relat Disord2023; 69: 104426.
36.
Aquilina-ReidCBrennanSCurry-HydeA, et al.Circular RNA expression and interaction patterns are perturbed in amyotrophic lateral sclerosis. Int J Mol Sci2022; 23: 14665.
37.
LiuXWangQZhaoJ, et al.Inflammation-related circRNA polymorphism and ischemic stroke prognosis. J Mol Neurosci2021; 71: 2126–2133.
38.
SaadawySFRaafatNSamyWM, et al.Role of Circ-ITCH gene polymorphisms and its expression in breast cancer susceptibility and prognosis. Diagnostics (Basel)2023; 13: 2033.
39.
XiXLiTHuangY, et al.RNA Biomarkers: frontier of precision medicine for cancer. Noncoding RNA2017; 3: 9.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
