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调节 FKBP5/FKBP51 和自噬可降低 HTT（亨廷顿蛋白）水平。

Modulating FKBP5/FKBP51 and autophagy lowers HTT (huntingtin) levels.

机构信息

The Buck Institute for Research on Aging, Novato, CA, USA.

School of Pharmacy and Health Sciences, Keck Graduate Institute, Claremont, CA, USA.

出版信息

Autophagy. 2021 Dec;17(12):4119-4140. doi: 10.1080/15548627.2021.1904489. Epub 2021 May 24.

DOI:10.1080/15548627.2021.1904489
PMID:34024231
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8726715/
Abstract

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, 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. : ACTB/β-actin: actin beta; AD: Alzheimer disease; BafA1: bafilomycin A; 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 -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.

摘要

目前，亨廷顿病（HD）的疾病修饰疗法侧重于降低突变 HTT（亨廷顿蛋白；mHTT）水平，免疫抑制剂雷帕霉素是一种用于衰老和神经疾病的有趣治疗方法。雷帕霉素与 FKBP1A/FKBP12 和 FKBP5/FKBP51 相互作用，抑制 MTORC1 复合物并增加细胞清除机制。HD 模型中 FKBP（FK506 结合蛋白）家族成员的水平是否改变，以及这些蛋白是否是 HD 的潜在治疗靶点，尚未得到研究。在这里，我们发现 FKBP5 的水平在 HD R6/2 和 zQ175 小鼠模型以及源自诱导多能干细胞的人类 HD 同源神经干细胞和中脑多巴胺能神经元中显著降低。此外，FKBP5 在 zQ175 小鼠和对照的纹状体和皮质中与 HTT 相互作用和共定位。重要的是，当我们通过遗传或药理学方法降低 FKBP5 的水平或活性时，我们观察到我们的同源人类 HD 干细胞模型中的 mHTT 水平降低。通过 siRNA 或药理学抑制降低 FKBP5 水平会增加 LC3-II 水平和巨自噬/自噬通量，表明自噬细胞清除机制负责降低 mHTT。与雷帕霉素不同，FKBP5 的抑制剂 SAFit2 的药理学抑制作用是 MTOR 独立的。此外，用 SAFit2 治疗 2 周可降低 HD R6/2 和 zQ175 小鼠模型中的 HTT 水平。我们的研究将 FKBP5 确定为参与 HD 发病机制的蛋白质，并将 FKBP5 鉴定为 HD 的潜在治疗靶点。 : ACTB/β-肌动蛋白：肌动蛋白β；AD：阿尔茨海默病；BafA1：巴佛霉素 A；BCA：二喹啉甲酸；BBB：血脑屏障；BSA：牛血清白蛋白；CoIP：共免疫沉淀；DMSO：二甲基亚砜；DTT：二硫苏糖醇；FKBP：FK506 结合蛋白；HD：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-（N-吗啉代）丙磺酸）；MSN：中脑多巴胺能神经元；mHTT：突变亨廷顿蛋白；MTOR：雷帕霉素靶蛋白激酶；NSC：神经干细胞；ON：过夜；PD：帕金森病；PPIase：肽基脯氨酰异构酶；polyQ：多聚谷氨酰胺；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；SQSTM1/p62：自噬体 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： vinculin；WT：同窝对照。

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