Deregulation of mTORC1-TFEB axis in human iPSC model of GBA1-associated Parkinson's disease.
Deregulation of mTORC1-TFEB axis in human iPSC model of GBA1-associated Parkinson's disease.
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DOI：
10.3389/fnins.2023.1152503
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发表时间：
2023
影响因子：
4.3
通讯作者：
Awad, Ola
中科院分区：
文献类型：
--
作者：
Mubariz, Fahad;Saadin, Afsoon;Lingenfelter, Nicholas;Sarkar, Chinmoy;Banerjee, Aditi;Lipinski, Marta M.;Awad, Ola
关键词：
GBA1基因突变是帕金森病(PD)最常见的遗传风险因素。与GBA1相关的帕金森病的神经退行性变化与自噬底物和聚集倾向蛋白的溶酶体清除缺陷有关。为了阐明导致PD蛋白病变的新机制，我们研究了GBA1突变对转录因子EB(TFEB)的影响，TFEB是自噬-溶酶体途径(ALP)的主要调节因子。利用PD患者的诱导多能干细胞(IPSCs)，我们检测了含有GBA1杂合突变的IPSC株和CRISPR/Cas9校正的等基因对照产生的多巴胺能神经元培养中TFEB的活性和对ALP的调节。我们的数据显示，在GBA1突变的神经元中，TFEB转录活性显著降低，许多基因在透明网络中的表达减弱，但在等基因校正的细胞中没有。在PD神经元中，我们还检测到哺乳动物靶标雷帕霉素复合体1(MTORC1)的活性增加，mTORC1是TFEB的主要上游负调控因子。MTORC1活性升高导致TFEB过度磷酸化，核转位减少。药物抑制可恢复TFEB活性，减轻内质网应激，减少α-突触核蛋白积聚，表明神经元原激活性改善。此外，用脂质底物还原化合物GENZ-123346处理后，突变神经元中mTORC1TFEB活性降低，TFEB表达增加，提示mTORC1TFEB的改变与脂质底物的积累有关。我们的研究揭示了一种通过GBA1突变导致帕金森病易感性的新机制，其中mTORC1-TFEB轴的解除调节介导了ALP功能障碍和随后的蛋白质病。这也表明，药物恢复TFEB活性可能是治疗GBA1相关神经变性的一种有前途的方法。
Mutations in the GBA1 gene are the single most frequent genetic risk factor for Parkinson’s disease (PD). Neurodegenerative changes in GBA1-associated PD have been linked to the defective lysosomal clearance of autophagic substrates and aggregate-prone proteins. To elucidate novel mechanisms contributing to proteinopathy in PD, we investigated the effect of GBA1 mutations on the transcription factor EB (TFEB), the master regulator of the autophagy-lysosomal pathway (ALP). Using PD patients’ induced-pluripotent stem cells (iPSCs), we examined TFEB activity and regulation of the ALP in dopaminergic neuronal cultures generated from iPSC lines harboring heterozygous GBA1 mutations and the CRISPR/Cas9-corrected isogenic controls. Our data showed a significant decrease in TFEB transcriptional activity and attenuated expression of many genes in the CLEAR network in GBA1 mutant neurons, but not in the isogenic gene-corrected cells. In PD neurons, we also detected increased activity of the mammalian target of rapamycin complex1 (mTORC1), the main upstream negative regulator of TFEB. Increased mTORC1 activity resulted in excess TFEB phosphorylation and decreased nuclear translocation. Pharmacological mTOR inhibition restored TFEB activity, decreased ER stress and reduced α-synuclein accumulation, indicating improvement of neuronal protiostasis. Moreover, treatment with the lipid substrate reducing compound Genz-123346, decreased mTORC1 activity and increased TFEB expression in the mutant neurons, suggesting that mTORC1-TFEB alterations are linked to the lipid substrate accumulation. Our study unveils a new mechanism contributing to PD susceptibility by GBA1 mutations in which deregulation of the mTORC1-TFEB axis mediates ALP dysfunction and subsequent proteinopathy. It also indicates that pharmacological restoration of TFEB activity could be a promising therapeutic approach in GBA1-associated neurodegeneration.
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影响因子：
3.5
作者：
Awad, Ola;Sarkar, Chinmoy;Feldman, Ricardo A.
通讯作者：
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影响因子：
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作者：
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影响因子：
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作者：
Peng Y;Liou B;Lin Y;Fannin V;Zhang W;Feldman RA;Setchell KDR;Grabowski GA;Sun Y
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Sun Y
在GBA-N370S帕金森氏菌IPSC衍生的多巴胺神经元中，ER应力和自噬扰动导致细胞外α-突触核蛋白升高。
影响因子：
5.9
作者：
Fernandes HJ;Hartfield EM;Christian HC;Emmanoulidou E;Zheng Y;Booth H;Bogetofte H;Lang C;Ryan BJ;Sardi SP;Badger J;Vowles J;Evetts S;Tofaris GK;Vekrellis K;Talbot K;Hu MT;James W;Cowley SA;Wade-Martins R
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Wade-Martins R