LRRTM3 Interacts with APP and BACE1 and Has Variants Associating with Late-Onset Alzheimer's Disease (LOAD)
PBN-AR
Instytucja
Instytut Medycyny Doświadczalnej i Klinicznej im. Mirosława Mossakowskiego Polskiej Akademii Nauk
Źródłowe zdarzenia ewaluacyjne
Informacje podstawowe
Główny język publikacji
en
Czasopismo
PLoS One
ISSN
1932-6203
EISSN
Wydawca
PUBLIC LIBRARY SCIENCE
DOI
URL
Rok publikacji
2013
Numer zeszytu
6
Strony od-do
64164-64164
Numer tomu
8
Identyfikator DOI
Liczba arkuszy
2,28
Słowa kluczowe
en
ALPHA-T-CATENIN
AMYLOID-PRECURSOR PROTEIN
GENETIC ASSOCIATION
BETA
CHROMOSOME-10
EXPRESSION
LINKAGE
BRAIN
MICE
CTNNA3
Open access
Tryb otwartego dostępu
Otwarte czasopismo
Wersja tekstu w otwartym dostępie
Wersja opublikowana
Licencja otwartego dostępu
Inna
Czas opublikowania w otwartym dostępie
Razem z publikacją
Data udostępnienia w sposób otwarty
Streszczenia
Język
en
Treść
Leucine rich repeat transmembrane protein 3 (LRRTM3) is member of a synaptic protein family. LRRTM3 is a nested gene within alpha-T catenin (CTNNA3) and resides at the linkage peak for late-onset Alzheimer's disease (LOAD) risk and plasma amyloid beta (Ab) levels. In-vitro knock-down of LRRTM3 was previously shown to decrease secreted Ab, 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 similar to 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.
Cechy publikacji
ORIGINAL_ARTICLE
Inne
System-identifier
588728
CrossrefMetadata from Crossref logo
Cytowania
Liczba prac cytujących tę pracę
Brak danych
Referencje
Liczba prac cytowanych przez tę pracę
Brak danych