Modulating FKBP5/FKBP51 and autophagy lowers HTT (huntingtin) levels.
Modulating FKBP5/FKBP51 and autophagy lowers HTT (huntingtin) levels.
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DOI：
10.1080/15548627.2021.1904489
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发表时间：
2021-12
期刊：
影响因子：
13.3
通讯作者：
Ellerby LM
中科院分区：
文献类型：
--
作者：
Bailus BJ;Scheeler SM;Simons J;Sanchez MA;Tshilenge KT;Creus-Muncunill J;Naphade S;Lopez-Ramirez A;Zhang N;Lakshika Madushani K;Moroz S;Loureiro A;Schreiber KH;Hausch F;Kennedy BK;Ehrlich ME;Ellerby LM
目前用于亨廷顿病（HD）的疾病修饰疗法集中于降低突变HTT（亨廷顿蛋白; mHTT）水平，并且免疫抑制剂药物雷帕霉素是用于衰老和神经系统疾病的有趣的治疗剂。雷帕霉素与FKBP1A/FKBP12和FKBP5/FKBP51相互作用，抑制MTORC 1复合物并增加细胞清除机制。尚未研究HD模型中FKBP（FK506结合蛋白）家族成员的水平是否发生变化，以及这些蛋白是否是HD的潜在治疗靶点。在这里，我们发现FKBP 5的水平在HD R6/2和zQ175小鼠模型以及人HD同基因神经干细胞和来源于诱导多能干细胞的中等多刺神经元中显著降低。此外，FKBP5与HTT在zQ175小鼠和对照的纹状体和皮质中相互作用并共定位。重要的是，当我们通过遗传或药理学方法降低FKBP5水平或活性时，我们在我们的同基因人HD干细胞模型中观察到mHTT水平降低。通过siRNA或药理学抑制降低FKBP5水平增加了LC 3-II水平和巨自噬/自噬通量，表明自噬细胞清除机制是mHTT降低的原因。与雷帕霉素不同，SAFit2（FKBP 5的抑制剂）的药理学抑制作用是MTOR独立的。此外，在HD R6/2和zQ175小鼠模型中，用SAFit2体内处理2周导致HTT水平降低。我们的研究确定FKBP5作为参与HD发病机制的蛋白质，并将FKBP5鉴定为HD的潜在治疗靶点。缩略语：ACTB/β-肌动蛋白：肌动蛋白β;广告：阿尔茨海默病; BafA1：巴弗洛霉素A1; BCA：二喹啉甲酸;血脑：血脑屏障;牛血清白蛋白：牛血清白蛋白; CoIP：免疫共沉淀;二甲基亚砜：二甲基亚砜; DTT：二硫苏糖醇; FKBP：FK506结合蛋白;高清：亨廷顿病; HTT：亨廷顿蛋白; iPSC：诱导多能干细胞; MAP1LC3/LC3：微管相关蛋白1轻链3; MAPT/tau：微管相关蛋白tau; MES：2-乙磺酸; MOPS：3-乙磺酸（N-吗啉代）丙磺酸）; MSN：中等多刺神经元; mHTT：突变亨廷顿蛋白; MTOR：雷帕霉素激酶的机制靶标; NSC：神经干细胞; ON：过夜; PD：帕金森病; PPIase：肽基-脯氨酰顺式/反式异构酶; polyQ：聚谷氨酰胺; PPP1R1B/DARPP-32：蛋白磷酸酶1调节抑制剂亚基1B; PTSD：创伤后应激障碍; RT：室温; SQSTM 1/p62：多价螯合体1; SDS-PAGE：十二烷基硫酸钠-聚丙烯酰胺凝胶电泳; TBST：Tris缓冲盐水，0.1%吐温20; TUBA：微管蛋白; ULK1：unc-51样自噬激活激酶1; VCL：粘着斑蛋白; WT：同窝对照。
Current disease-modifying therapies for Huntington disease (HD) focus on lowering mutant HTT (huntingtin; mHTT) levels, and the immunosuppressant drug rapamycin is an intriguing therapeutic for aging and neurological disorders. Rapamycin interacts with FKBP1A/FKBP12 and FKBP5/FKBP51, inhibiting the MTORC1 complex and increasing cellular clearance mechanisms. Whether the levels of FKBP (FK506 binding protein) family members are altered in HD models and if these proteins are potential therapeutic targets for HD have not been investigated. Here, we found levels of FKBP5 are significantly reduced in HD R6/2 and zQ175 mouse models and human HD isogenic neural stem cells and medium spiny neurons derived from induced pluripotent stem cells. Moreover, FKBP5 interacts and colocalizes with HTT in the striatum and cortex of zQ175 mice and controls. Importantly, when we decreased FKBP5 levels or activity by genetic or pharmacological approaches, we observed reduced levels of mHTT in our isogenic human HD stem cell model. Decreasing FKBP5 levels by siRNA or pharmacological inhibition increased LC3-II levels and macroautophagic/autophagic flux, suggesting autophagic cellular clearance mechanisms are responsible for mHTT lowering. Unlike rapamycin, the effect of pharmacological inhibition with SAFit2, an inhibitor of FKBP5, is MTOR independent. Further, in vivo treatment for 2 weeks with SAFit2, results in reduced HTT levels in both HD R6/2 and zQ175 mouse models. Our studies establish FKBP5 as a protein involved in the pathogenesis of HD and identify FKBP5 as a potential therapeutic target for HD. Abbreviations : ACTB/β-actin: actin beta; AD: Alzheimer disease; BafA1: bafilomycin A1; BCA: bicinchoninic acid; BBB: blood brain barrier; BSA: bovine serum albumin; CoIP: co-immunoprecipitation; DMSO: dimethyl sulfoxide; DTT: dithiothreitol; FKBPs: FK506 binding proteins; HD: Huntington disease; HTT: huntingtin; iPSC: induced pluripotent stem cells; MAP1LC3/LC3:microtubule associated protein 1 light chain 3; MAPT/tau: microtubule associated protein tau; MES: 2-ethanesulfonic acid; MOPS: 3-(N-morphorlino)propanesulfonic acid); MSN: medium spiny neurons; mHTT: mutant huntingtin; MTOR: mechanistic target of rapamycin kinase; NSC: neural stem cells; ON: overnight; PD: Parkinson disease; PPIase: peptidyl-prolyl cis/trans-isomerases; polyQ: polyglutamine; PPP1R1B/DARPP-32: protein phosphatase 1 regulatory inhibitor subunit 1B; PTSD: post-traumatic stress disorder; RT: room temperature; SQSTM1/p62: sequestosome 1; SDS-PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; TBST:Tris-buffered saline, 0.1% Tween 20; TUBA: tubulin; ULK1: unc-51 like autophagy activating kinase 1; VCL: vinculin; WT: littermate controls.
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影响因子：
4
作者：
Cioffi, Donna L.;Hubler, Tina R.;Scammell, Jonathan G.
通讯作者：
Scammell, Jonathan G.
影响因子：
9.3
作者：
Al-Ramahi I;Lu B;Di Paola S;Pang K;de Haro M;Peluso I;Gallego-Flores T;Malik NT;Erikson K;Bleiberg BA;Avalos M;Fan G;Rivers LE;Laitman AM;Diaz-García JR;Hild M;Palacino J;Liu Z;Medina DL;Botas J
通讯作者：
Botas J
影响因子：
3.4
作者：
Blair, Laura J.;Criado-Marrero, Marangelie;Dickey, Chad A.
通讯作者：
Dickey, Chad A.
DOI：
10.1371/currents.hd.0242d2e7ad72225efa72f6964589369a
发表时间：
2014-04-15
期刊：
PLoS currents
影响因子：
--
作者：
An, Mahru C;O'Brien, Robert N;Ellerby, Lisa M
通讯作者：
Ellerby, Lisa M
影响因子：
16.6
作者：
Balsevich G;Häusl AS;Meyer CW;Karamihalev S;Feng X;Pöhlmann ML;Dournes C;Uribe-Marino A;Santarelli S;Labermaier C;Hafner K;Mao T;Breitsamer M;Theodoropoulou M;Namendorf C;Uhr M;Paez-Pereda M;Winter G;Hausch F;Chen A;Tschöp MH;Rein T;Gassen NC;Schmidt MV
通讯作者：
Schmidt MV