期刊
NATURE MEDICINE
卷 24, 期 5, 页码 598-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41591-018-0013-y
关键词
-
资金
- SYNAPSIS Foundation
- Beatrice Ederer-Weber Stiftung
- Floshield Foundation
- Alzheimer's Association [NIRG-15-363964]
- Foundation Jerome Lejeune, Spanish Ministerio de Educacion y Competitividad [BFU2014-53093]
- Spanish Ministerio de Economia, Industria y Competitividad
- FEDER programme from the EU [SAF2014-59469-R]
- CIBERNED
- SYNAPSIS Foundation Fellowship for Advanced PostDocs
- Heidi Seiler-Stiftung foundation
- Spanish Institute of Health Carlos III (ISCIII) [CP14/00229]
- FPI PhD studentship from MINECO
The chances to develop Alzheimer's disease (AD) result from a combination of genetic and non-genetic risk factors(1), the latter likely being mediated by epigenetic mechanisms(2). In the past, genome-wide association studies (GWAS) have identified an important number of risk loci associated with AD pathology(3), but a causal relationship remains difficult to establish. In contrast, locus-specific or epigenome-wide association studies (EWAS) have revealed site-specific epigenetic alterations, which provide mechanistic insights for a particular risk gene but often lack the statistical power of GWAS(4). Here, combining both approaches, we report a previously unidentified association of the peptidase M20-domain-containing protein 1 (PM20D1) with AD. We find that PM20D1 is a methylation and expression quantitative trait locus coupled to an AD-risk associated haplotype, which displays enhancer-like characteristics and contacts the PM20D1 promoter via a haplotype-dependent, CCCTC-binding-factor-mediated chromatin loop. Furthermore, PM20D1 is increased following AD-related neurotoxic insults at symptomatic stages in the APP/PS1 mouse model of AD and in human patients with AD who are carriers of the non-risk haplotype. In line, genetically increasing or decreasing the expression of PM20D1 reduces and aggravates AD-related pathologies, respectively. These findings suggest that in a particular genetic background, PM20D1 contributes to neuroprotection against AD.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据