Mutant Presenilin 1 Dysregulates Exosomal Proteome Cargo Produced by Human-Induced Pluripotent Stem Cell Neurons.
Mutant Presenilin 1 Dysregulates Exosomal Proteome Cargo Produced by Human-Induced Pluripotent Stem Cell Neurons.
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DOI：
10.1021/acsomega.1c00660
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发表时间：
2021-05-25
期刊：
影响因子：
4.1
通讯作者：
Hook V
中科院分区：
文献类型：
--
作者：
Podvin S;Jones A;Liu Q;Aulston B;Mosier C;Ames J;Winston C;Lietz CB;Jiang Z;O'Donoghue AJ;Ikezu T;Rissman RA;Yuan SH;Hook V
过度磷酸化tau蛋白（p-Tau）的积累和增殖是阿尔茨海默病（AD）神经退行性变的神经病理学标志。细胞外囊泡，即外泌体，已被证明可以启动tau蛋白在大脑中的繁殖。值得注意的是，来自人诱导多能干细胞（iPSC）神经元的外泌体表达AD家族性早老素1 （mPS1）的A246E突变形式，在体内注射后能够在小鼠大脑中诱导tau沉积。为了深入了解参与tau病理学传播的外泌体蛋白质组，本研究对表达A246E mPS1的人类iPSC神经元产生的外泌体进行了蛋白质组学分析。值得注意的是，mPS1改变了外泌体货物蛋白的特征，导致(1)蛋白质只存在于mPS1外泌体中，而不存在于对照组中，(2)mPS1外泌体中缺乏只存在于对照组中的蛋白质，(3)与对照组相比，mPS1外泌体中共享的蛋白质上调或下调。这些结果表明，mPS1失调外泌体的蛋白质组货物，导致参与细胞外基质和蛋白酶功能的蛋白质获得，参与RNA和蛋白质翻译系统以及蛋白酶体和相关功能的蛋白质缺失，并结合共享蛋白的上调和下调，包括淀粉样蛋白前体蛋白的上调。值得注意的是，mPS1神经元来源的外泌体显示出参与调节p-tau状态的蛋白磷酸酶和激酶的改变。mPS1对外泌体货物蛋白的失调可能与mPS1神经元来源的外泌体传播tau病理的能力有关。
The accumulation and propagation of hyperphosphorylated tau (p-Tau) is a neuropathological hallmark occurring with neurodegeneration of Alzheimer’s disease (AD). Extracellular vesicles, exosomes, have been shown to initiate tau propagation in the brain. Notably, exosomes from human-induced pluripotent stem cell (iPSC) neurons expressing the AD familial A246E mutant form of presenilin 1 (mPS1) are capable of inducing tau deposits in the mouse brain after in vivo injection. To gain insights into the exosome proteome cargo that participates in propagating tau pathology, this study conducted proteomic analysis of exosomes produced by human iPSC neurons expressing A246E mPS1. Significantly, mPS1 altered the profile of exosome cargo proteins to result in (1) proteins present only in mPS1 exosomes and not in controls, (2) the absence of proteins in the mPS1 exosomes which were present only in controls, and (3) shared proteins which were upregulated or downregulated in the mPS1 exosomes compared to controls. These results show that mPS1 dysregulates the proteome cargo of exosomes to result in the acquisition of proteins involved in the extracellular matrix and protease functions, deletion of proteins involved in RNA and protein translation systems along with proteasome and related functions, combined with the upregulation and downregulation of shared proteins, including the upregulation of amyloid precursor protein. Notably, mPS1 neuron-derived exosomes displayed altered profiles of protein phosphatases and kinases involved in regulating the status of p-tau. The dysregulation of exosome cargo proteins by mPS1 may be associated with the ability of mPS1 neuron-derived exosomes to propagate tau pathology.
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影响因子：
64.8
作者：
Berns DS;DeNardo LA;Pederick DT;Luo L
通讯作者：
Luo L
DOI：
10.1111/acer.13362
发表时间：
2017-05
期刊：
Alcoholism, clinical and experimental research
影响因子：
--
作者：
Adkins AE;Hack LM;Bigdeli TB;Williamson VS;McMichael GO;Mamdani M;Edwards AC;Aliev F;Chan RF;Bhandari P;Raabe RC;Alaimo JT;Blackwell GG;Moscati A;Poland RS;Rood B;Patterson DG;Walsh D;Collaborative Study of the Genetics of Alcoholism Consortium;Whitfield JB;Zhu G;Montgomery GW;Henders AK;Martin NG;Heath AC;Madden PAF;Frank J;Ridinger M;Wodarz N;Soyka M;Zill P;Ising M;Nöthen MM;Kiefer F;Rietschel M;German Study of the Genetics of Addiction Consortium;Gelernter J;Sherva R;Koesterer R;Almasy L;Zhao H;Kranzler HR;Farrer LA;Maher BS;Prescott CA;Dick DM;Bacanu SA;Mathies LD;Davies AG;Vladimirov VI;Grotewiel M;Bowers MS;Bettinger JC;Webb BT;Miles MF;Kendler KS;Riley BP
通讯作者：
Riley BP
影响因子：
3.2
作者：
Barrera-Ocampo A;Arlt S;Matschke J;Hartmann U;Puig B;Ferrer I;Zürbig P;Glatzel M;Sepulveda-Falla D;Jahn H
通讯作者：
Jahn H
影响因子：
11
作者：
Bis JC;Jian X;Kunkle BW;Chen Y;Hamilton-Nelson KL;Bush WS;Salerno WJ;Lancour D;Ma Y;Renton AE;Marcora E;Farrell JJ;Zhao Y;Qu L;Ahmad S;Amin N;Amouyel P;Beecham GW;Below JE;Campion D;Cantwell L;Charbonnier C;Chung J;Crane PK;Cruchaga C;Cupples LA;Dartigues JF;Debette S;Deleuze JF;Fulton L;Gabriel SB;Genin E;Gibbs RA;Goate A;Grenier-Boley B;Gupta N;Haines JL;Havulinna AS;Helisalmi S;Hiltunen M;Howrigan DP;Ikram MA;Kaprio J;Konrad J;Kuzma A;Lander ES;Lathrop M;Lehtimäki T;Lin H;Mattila K;Mayeux R;Muzny DM;Nasser W;Neale B;Nho K;Nicolas G;Patel D;Pericak-Vance MA;Perola M;Psaty BM;Quenez O;Rajabli F;Redon R;Reitz C;Remes AM;Salomaa V;Sarnowski C;Schmidt H;Schmidt M;Schmidt R;Soininen H;Thornton TA;Tosto G;Tzourio C;van der Lee SJ;van Duijn CM;Valladares O;Vardarajan B;Wang LS;Wang W;Wijsman E;Wilson RK;Witten D;Worley KC;Zhang X;Alzheimer’s Disease Sequencing Project;Bellenguez C;Lambert JC;Kurki MI;Palotie A;Daly M;Boerwinkle E;Lunetta KL;Destefano AL;Dupuis J;Martin ER;Schellenberg GD;Seshadri S;Naj AC;Fornage M;Farrer LA
通讯作者：
Farrer LA
影响因子：
64.8
作者：
Ahel, Ivan;Ahel, Dragana;West, Stephen C.
通讯作者：
West, Stephen C.