Regional expression of genes mediating trans-synaptic alpha-synuclein transfer predicts regional atrophy in Parkinson disease.
Regional expression of genes mediating trans-synaptic alpha-synuclein transfer predicts regional atrophy in Parkinson disease.
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DOI：
10.1016/j.nicl.2018.01.009
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Raj A
中科院分区：
文献类型：
--
作者：
Freeze B;Acosta D;Pandya S;Zhao Y;Raj A
帕金森病的发病机制涉及多个基因，但这些基因的区域表达与整个大脑的区域功能障碍之间的关系尚不清楚。我们通过联合分析帕金森进展标记物计划的高分辨率磁共振成像数据和Allen脑图谱的区域基因微阵列表达数据来解决这个问题。区域性脑萎缩和基因表达被共同登记在一个共同的86个区域脑图谱中，并进行稳健的多变量回归分析以确定区域性脑萎缩的遗传预测因素。我们分析的候选基因包括GWA值最高的基因，以及涉及跨突触α-突触核蛋白转移和常染色体隐性帕金森病的基因。我们确定了三个具有表达模式的基因，它们是区域性脑萎缩的高度显著的预测因子。两个最重要的预测因子是LAG3和RAB5A，这两个基因与跨突触突触核蛋白转移有关。其他经过充分验证的PD相关基因没有预测区域性萎缩的表达模式，这表明它们可能起到其他作用，如疾病启动因子。联合体积分析和微阵列分析确定预测帕金森病萎缩模式的基因表达模式。最具预测性的基因LAG3和RAB5A与跨突触α-突触核蛋白转移有关。α-突触核蛋白和其他PD相关基因的表达模式不能预测萎缩。
Multiple genes have been implicated in Parkinson disease pathogenesis, but the relationship between regional expression of these genes and regional dysfunction across the brain is unknown. We address this question by joint analysis of high resolution magnetic resonance imaging data from the Parkinson's Progression Markers Initiative and regional genetic microarray expression data from the Allen Brain Atlas. Regional brain atrophy and genetic expression was co-registered to a common 86 region brain atlas and robust multivariable regression analysis was performed to identify genetic predictors of regional brain atrophy. Top candidate genes from GWAS analysis, as well as genes implicated in trans-synaptic alpha-synuclein transfer and autosomal recessive PD were included in our analysis. We identify three genes with expression patterns that are highly significant predictors of regional brain atrophy. The two most significant predictors are LAG3 and RAB5A, genes implicated in trans-synaptic synuclein transfer. Other well-validated PD-related genes do not have expression patterns that predict regional atrophy, suggesting that they may serve other roles such as disease initiation factors. Joint volumetric and microarray analysis identifies gene expression patterns that predict the PD atrophy pattern. The most highly predictive genes, LAG3 and RAB5A, are implicated in trans-synaptic alpha-synuclein transfer. The expression patterns of alpha-synuclein and otherPD-related genes do not predict atrophy.
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影响因子：
34.7
作者：
Frost, Bess;Diamond, Marc I.
通讯作者：
Diamond, Marc I.
影响因子：
168.9
作者：
Chartier-Harlin, MC;Kachergus, J;Destée, A
通讯作者：
Destée, A
DOI：
10.1126/science.aah3374
发表时间：
2016-09-30
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Mao X;Ou MT;Karuppagounder SS;Kam TI;Yin X;Xiong Y;Ge P;Umanah GE;Brahmachari S;Shin JH;Kang HC;Zhang J;Xu J;Chen R;Park H;Andrabi SA;Kang SU;Gonçalves RA;Liang Y;Zhang S;Qi C;Lam S;Keiler JA;Tyson J;Kim D;Panicker N;Yun SP;Workman CJ;Vignali DA;Dawson VL;Ko HS;Dawson TM
通讯作者：
Dawson TM
影响因子：
5.7
作者：
Fischl, Bruce
通讯作者：
Fischl, Bruce
影响因子：
30.8
作者：
Nalls, Mike A.;Pankratz, Nathan;Lill, Christina M.;Do, Chuong B.;Hernandez, Dena G.;Saad, Mohamad;DeStefano, Anita L.;Kara, Eleanna;Bras, Jose;Sharma, Manu;Schulte, Claudia;Keller, Margaux F.;Arepalli, Sampath;Letson, Christopher;Edsall, Connor;Stefansson, Hreinn;Liu, Xinmin;Pliner, Hannah;Lee, Joseph H.;Cheng, Rong;Ikram, M. Arfan;Ioannidis, John P. A.;Hadjigeorgiou, Georgios M.;Bis, Joshua C.;Martinez, Maria;Perlmutter, Joel S.;Goate, Alison;Marder, Karen;Fiske, Brian;Sutherland, Margaret;Xiromerisiou, Georgia;Myers, Richard H.;Clark, Lorraine N.;Stefansson, Kari;Hardy, John A.;Heutink, Peter;Chen, Honglei;Wood, Nicholas W.;Houlden, Henry;Payami, Haydeh;Brice, Alexis;Scott, William K.;Gasser, Thomas;Bertram, Lars;Eriksson, Nicholas;Foroud, Tatiana;Singleton, Andrew B.
通讯作者：
Singleton, Andrew B.