Dataset Information

Methylation Profiling RIN3 and MEF2C Identifies Epigenetic Marks Associated with Sporadic Early Onset Alzheimer's Disease.

ABSTRACT: A number of genetic loci associate with early onset Alzheimer's disease (EOAD); however, the drivers of this disease remains enigmatic. Genome wide association and in vivo modeling have shown that loss-of-function, e.g., ABCA7, reduced levels of SIRT1 and MEFF2C, or increased levels of PTK2? confer risk or link to the pathogenies. It is known that DNA methylation can profoundly affect gene expression and can impact on the composition of the proteome; therefore, the aim of this study is to assess if genes associated with sporadic EOAD (sEOAD) are differentially methylated. Epi-profiles of DNA extracted from blood and cortex were compared using a pyrosequencing platform. We identified significant group-wide hypomethylation in AD blood when compared to controls for 7 CpGs located within the 3'UTR of RIN3 (CpG1 p?=?0.019, CpG2 p?=?0.018, CpG3 p?=?0.012, CpG4 p?=?0.009, CpG5 p?=?0.002, CpG6 p?=?0.018, and CpG7 p?=?0.013, respectively; AD/Control n?=?22/26; Male/Female n?=?27/21). Observed effects were not gender specific. No group wide significant differences were found in the promoter methylation of PTK2?, ABCA7, SIRT1, or MEF2C, genes known to associate with late onset AD. A rare and significant difference in methylation was observed for one CpG located upstream of the MEF2C promoter in one AD individual only (22% reduction in methylation, p?=?2.0E-10; Control n?=?26, AD n?=?25, Male/Female n?=?29/22). It is plausible aberrant methylation may mark sEOAD in blood and may manifest in some individuals as rare epi-variants for genes linked to sEOAD.

SUBMITTER: Boden KA

PROVIDER: S-EPMC6159661 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Methylation Profiling RIN3 and MEF2C Identifies Epigenetic Marks Associated with Sporadic Early Onset Alzheimer's Disease.

Boden Kirsty A KA Barber Imelda S IS Clement Naomi N Patel Tulsi T Guetta-Baranes Tamar T Brookes Keeley J KJ Chappell Sally S Craigon Jim J Chapman Natalie H NH Morgan Kevin K Seymour Graham B GB Bottley Andrew A

Journal of Alzheimer's disease reports 20170913 1

A number of genetic loci associate with early onset Alzheimer's disease (EOAD); however, the drivers of this disease remains enigmatic. Genome wide association and <i>in vivo</i> modeling have shown that loss-of-function, e.g., ABCA7, reduced levels of SIRT1 and MEFF2C, or increased levels of PTK2β confer risk or link to the pathogenies. It is known that DNA methylation can profoundly affect gene expression and can impact on the composition of the proteome; therefore, the aim of this study is to ...[more]

PMID: 30480232

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Project description:BACKGROUND:In Alzheimer's Disease (AD), about one-third of the risk genes identified by GWAS encode proteins that function predominantly in the endocytic pathways. Among them, the Ras and Rab Interactor 3(RIN3) is a guanine nucleotide exchange factor (GEF) for the Rab5 small GTPase family and has been implicated to be a risk factor for both late onset AD (LOAD) and sporadic early onset AD (sEOAD). However, how RIN3 is linked to AD pathogenesis is currently undefined. METHODS:Quantitative PCR and immunoblotting were used to measure the RIN3 expression level in mouse brain tissues and cultured basal forebrain cholinergic neuron (BFCNs). Immunostaining was used to define subcellular localization of RIN3 and to visualize endosomal changes in cultured primary BFCNs and PC12 cells. Recombinant flag-tagged RIN3 protein was purified from HEK293T cells and was used to define RIN3-interactomes by mass spectrometry. RIN3-interacting partners were validated by co-immunoprecipitation, immunofluorescence and yeast two hybrid assays. Live imaging of primary neurons was used to examine axonal transport of amyloid precursor protein (APP) and ?-secretase 1 (BACE1). Immunoblotting was used to detect protein expression, processing of APP and phosphorylated forms of Tau. RESULTS:We have shown that RIN3 mRNA level was significantly increased in the hippocampus and cortex of APP/PS1 mouse brain. Basal forebrain cholinergic neurons (BFCNs) cultured from E18 APP/PS1 mouse embryos also showed increased RIN3 expression accompanied by early endosome enlargement. In addition, via its proline rich domain, RIN3 recruited BIN1(bridging integrator 1) and CD2AP (CD2 associated protein), two other AD risk factors, to early endosomes. Interestingly, overexpression of RIN3 or CD2AP promoted APP cleavage to increase its carboxyl terminal fragments (CTFs) in PC12 cells. Upregulation of RIN3 or the neuronal isoform of BIN1 increased phosphorylated Tau level. Therefore, upregulation of RIN3 expression promoted accumulation of APP CTFs and increased phosphorylated Tau. These effects by RIN3 was rescued by the expression of a dominant negative Rab5 (Rab5S34N) construct. Our study has thus pointed to that RIN3 acts through Rab5 to impact endosomal trafficking and signaling. CONCLUSION:RIN3 is significantly upregulated and correlated with endosomal dysfunction in APP/PS1 mouse. Through interacting with BIN1 and CD2AP, increased RIN3 expression alters axonal trafficking and procession of APP. Together with our previous studies, our current work has thus provided important insights into the role of RIN3 in regulating endosomal signaling and trafficking.

Dataset Information

Methylation Profiling RIN3 and MEF2C Identifies Epigenetic Marks Associated with Sporadic Early Onset Alzheimer's Disease.

Publications

Methylation Profiling RIN3 and MEF2C Identifies Epigenetic Marks Associated with Sporadic Early Onset Alzheimer's Disease.

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