Linnertz Colton, Lutz Michael W, Ervin John F, Allen Jawara, Miller Natalie R, Welsh-Bohmer Kathleen A, Roses Allen D, Chiba-Falek Ornit
Department of Neurology, Duke University Medical Center, Durham, NC 27710, USA.
Department of Neurology, Duke University Medical Center, Durham, NC 27710, USA, Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Duke University Medical Center, Durham, NC 27710, USA.
Hum Mol Genet. 2014 Sep 15;23(18):4814-21. doi: 10.1093/hmg/ddu196. Epub 2014 Apr 28.
The molecular genetic basis that leads to Lewy Body (LB) pathology in 15-20% of Alzheimer disease cases (LBV/AD) was largely unknown. Alpha-synuclein (SNCA) and Leucine-rich repeat kinase2 (LRRK2) have been implicated in the pathogenesis of Parkinson's disease (PD), the prototype of LB spectrum disorders. We tested the association of SNCA variants with LB pathology in AD. We then stratified the SNCA association analyses by LRRK2 genotype. We also investigated the expression regulation of SNCA and LRRK2 in relation to LB pathology. We evaluated the differences in SNCA-mRNA and LRRK2-mRNA levels as a function of LB pathology in the temporal cortex (TC) from autopsy-confirmed LBV/AD cases and AD controls. We further investigated the cis-effect of the LB pathology-associated genetic variants within the SNCA and LRRK2 loci on the mRNA expression of these genes. SNCA SNPs rs3857059 and rs2583988 showed significant associations with increased risk for LB pathology. When the analyses were stratified by LRRK2-rs1491923 genotype, the associations became stronger for both SNPs and an association was also observed with rs2619363. Expression analysis demonstrated that SNCA- and LRRK2-mRNA levels were significantly higher in TC from LBV/AD brains compared with AD controls. Furthermore, SNCA-mRNA expression level in the TC was associated with rs3857059; homozygotes for the minor allele showed significant higher expression. LRRK2-transcript levels were increased in carriers of rs1491923 minor allele. Our findings demonstrated that SNCA contributes to LB pathology in AD patients, possibly via interaction with LRRK2, and suggested that expression regulation of these genes may be the molecular basis underlying the observed LB associations.
在15%-20%的阿尔茨海默病病例（路易体变异型阿尔茨海默病，LBV/AD）中导致路易体（LB）病理改变的分子遗传基础在很大程度上尚不清楚。α-突触核蛋白（SNCA）和富含亮氨酸重复激酶2（LRRK2）与帕金森病（PD）的发病机制有关，PD是LB谱系障碍的原型。我们测试了SNCA变异与AD中路易体病理改变的关联。然后我们根据LRRK2基因型对SNCA关联分析进行分层。我们还研究了SNCA和LRRK2与路易体病理改变相关的表达调控。我们评估了经尸检确诊的LBV/AD病例和AD对照的颞叶皮质（TC）中SNCA-mRNA和LRRK2-mRNA水平随路易体病理改变的差异。我们进一步研究了SNCA和LRRK2基因座内与路易体病理改变相关的遗传变异对这些基因mRNA表达的顺式效应。SNCA单核苷酸多态性（SNP）rs3857059和rs2583988与路易体病理改变风险增加显著相关。当根据LRRK2-rs1491923基因型进行分层分析时，两个SNP的关联都变得更强，并且还观察到与rs2619363的关联。表达分析表明，与AD对照相比，LBV/AD脑TC中的SNCA和LRRK2-mRNA水平显著更高。此外，TC中的SNCA-mRNA表达水平与rs3857059相关；次要等位基因的纯合子显示出显著更高的表达。rs1491923次要等位基因携带者的LRRK2转录水平升高。我们的研究结果表明，SNCA可能通过与LRRK2相互作用促成AD患者的路易体病理改变，并提示这些基因的表达调控可能是所观察到的路易体关联的分子基础。
