Dataset Information

LRRTM3 interacts with APP and BACE1 and has variants associating with late-onset Alzheimer's disease (LOAD).

ABSTRACT: Leucine rich repeat transmembrane protein 3 (LRRTM3) is member of a synaptic protein family. LRRTM3 is a nested gene within ?-T catenin (CTNNA3) and resides at the linkage peak for late-onset Alzheimer's disease (LOAD) risk and plasma amyloid ? (A?) levels. In-vitro knock-down of LRRTM3 was previously shown to decrease secreted A?, although the mechanism of this is unclear. In SH-SY5Y cells overexpressing APP and transiently transfected with LRRTM3 alone or with BACE1, we showed that LRRTM3 co-localizes with both APP and BACE1 in early endosomes, where BACE1 processing of APP occurs. Additionally, LRRTM3 co-localizes with APP in primary neuronal cultures from Tg2576 mice transduced with LRRTM3-expressing adeno-associated virus. Moreover, LRRTM3 co-immunoprecipitates with both endogenous APP and overexpressed BACE1, in HEK293T cells transfected with LRRTM3. SH-SY5Y cells with knock-down of LRRTM3 had lower BACE1 and higher CTNNA3 mRNA levels, but no change in APP. Brain mRNA levels of LRRTM3 showed significant correlations with BACE1, CTNNA3 and APP in ?400 humans, but not in LRRTM3 knock-out mice. Finally, we assessed 69 single nucleotide polymorphisms (SNPs) within and flanking LRRTM3 in 1,567 LOADs and 2,082 controls and identified 8 SNPs within a linkage disequilibrium block encompassing 5'UTR-Intron 1 of LRRTM3 that formed multilocus genotypes (MLG) with suggestive global association with LOAD risk (p?=?0.06), and significant individual MLGs. These 8 SNPs were genotyped in an independent series (1,258 LOADs and 718 controls) and had significant global and individual MLG associations in the combined dataset (p?=?0.02-0.05). Collectively, these results suggest that protein interactions between LRRTM3, APP and BACE1, as well as complex associations between mRNA levels of LRRTM3, CTNNA3, APP and BACE1 in humans might influence APP metabolism and ultimately risk of AD.

SUBMITTER: Lincoln S

PROVIDER: S-EPMC3672107 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

LRRTM3 interacts with APP and BACE1 and has variants associating with late-onset Alzheimer's disease (LOAD).

Lincoln Sarah S Allen Mariet M Cox Claire L CL Walker Louise P LP Malphrus Kimberly K Qiu Yushi Y Nguyen Thuy T Rowley Christopher C Kouri Naomi N Crook Julia J Pankratz V Shane VS Younkin Samuel S Younkin Linda L Carrasquillo Minerva M Zou Fanggeng F Abdul-Hay Samer O SO Springer Wolfdieter W Sando Sigrid B SB Aasly Jan O JO Barcikowska Maria M Wszolek Zbigniew K ZK Lewis Jada M JM Dickson Dennis D Graff-Radford Neill R NR Petersen Ronald C RC Eckman Elizabeth E Younkin Steven G SG Ertekin-Taner Nilüfer N

PloS one 20130604 6

Leucine rich repeat transmembrane protein 3 (LRRTM3) is member of a synaptic protein family. LRRTM3 is a nested gene within α-T catenin (CTNNA3) and resides at the linkage peak for late-onset Alzheimer's disease (LOAD) risk and plasma amyloid β (Aβ) levels. In-vitro knock-down of LRRTM3 was previously shown to decrease secreted Aβ, although the mechanism of this is unclear. In SH-SY5Y cells overexpressing APP and transiently transfected with LRRTM3 alone or with BACE1, we showed that LRRTM3 co-l ...[more]

PMID: 23750206

Similar Datasets

Project description:Abstract Introduction As new late‐onset Alzheimer's disease (LOAD) genetic risk loci are identified and brain cell–type specific omics data becomes available, there is an unmet need for a bioinformatics framework to prioritize genes and variants for testing in single‐cell molecular profiling experiments and validation using disease models and gene editing technologies. Prior work has characterized and prioritized active enhancers located in LOAD‐genome‐wide association study (GWAS) regions and their potential interactions with candidate genes. The current study extends this work by focusing on single nucleotide polymorphisms (SNPs) within these LOAD enhancers and their impact on altering transcription factor (TF) binding. The proposed bioinformatics pipeline progresses from SNPs located in LOAD‐GWAS regions to a filtered set of candidate regulatory SNPs that have a predicted strong effect on TF binding. Methods Active enhancers within LOAD‐associated regions were identified and SNPs located in the enhancers were catalogued. SNPs that disrupt TF binding sites were prioritized and the respective TFs were filtered to include only those that were expressed in brain tissues relevant to LOAD. The TFs binding to the corresponding sequence was further confirmed by ChIP‐seq signals. Finally, the high‐priority candidate SNPs were evaluated as expression quantitative trait loci (eQTLs) in disease‐relevant tissues. Results We catalogued 61 strong enhancers in LOAD‐GWAS regions encompassing 326 SNPs and 104 TF binding sites. Seventy‐seven and 78 of the TFs were expressed in brain and monocytes, respectively, out of which 19 TF‐binding sites showed ChIP‐seq signals. Eleven SNPs were found to interrupt with TF binding out of which three SNPs were also significant eQTL. Discussion This study provides a framework to catalogue noncoding variations in enhancers located in LOAD‐GWAS loci and characterize their likelihood to perturb TF binding. The approach integrates multiple data types to characterize and prioritize SNPs for putative regulatory function using single‐cell multi‐omics assays and gene editing.

Dataset Information

LRRTM3 interacts with APP and BACE1 and has variants associating with late-onset Alzheimer's disease (LOAD).

Publications

LRRTM3 interacts with APP and BACE1 and has variants associating with late-onset Alzheimer's disease (LOAD).

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets