澳大利亚沃尔特和伊丽莎·霍尔医学研究所Seth L. Masters小组在研究中取得进展。他们发现TDP-43能够通过mPTP触发线粒体DNA释放以激活肌萎缩性侧索硬化症(ALS)中的环状鸟苷单磷酸(GMP)-AMP合酶(cGAS) / STING。2020年10月7日,《细胞》杂志发表了这一成果。
他们表示,当TDP-43侵入线粒体并通过通透性过渡孔释放DNA时,这种炎症就由胞质DNA传感器cGAS驱动。cGAS及其下游信号配体STING的药理抑制或遗传缺失可防止TDP-43在诱导多能干细胞(iPSC)来源的运动神经元和TDP-43突变小鼠中诱导核因子κB(NF-κB)和I型干扰素(IFN)的上调。最后,他们记录了患者脊髓样品中特定cGAS信号代谢产物cGAMP的水平升高,这可能是mtDNA释放和ALS中cGAS / STING激活的生物标志物。
他们的结果确定了mtDNA释放和cGAS / STING激活是TDP-43相关病理的关键决定因素,并证明了在ALS中靶向该途径的潜力。
据悉,TDP-43的细胞质积累是许多ALS的疾病标志,伴有与NF-κB和IFN通路上调相关的神经炎性细胞因子。
附:英文原文
Title: TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS
Author: Chien-Hsiung Yu, Sophia Davidson, Cassandra R. Harapas, James B. Hilton, Michael J. Mlodzianoski, Pawat Laohamonthonkul, Cynthia Louis, Ronnie Ren Jie Low, Jonas Moecking, Dominic De Nardo, Katherine R. Balka, Dale J. Calleja, Fiona Moghaddas, Erya Ni, Catriona A. McLean, Andre L. Samson, Shiraz Tyebji, Christopher J. Tonkin, Christopher R. Bye, Bradley J. Turner, Genevieve Pepin, Michael P. Gantier, Kelly L. Rogers, Kate McArthur, Peter J. Crouch, Seth L. Masters
Issue&Volume: 2020-10-07
Abstract: Cytoplasmic accumulation of TDP-43 is a disease hallmark for many cases of amyotrophic lateral sclerosis (ALS), associated with a neuroinflammatory cytokine profile related to upregulation of nuclear factor κB (NF-κB) and type I interferon (IFN) pathways. Here we show that this inflammation is driven by the cytoplasmic DNA sensor cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) when TDP-43 invades mitochondria and releases DNA via the permeability transition pore. Pharmacologic inhibition or genetic deletion of cGAS and its downstream signaling partner STING prevents upregulation of NF-κB and type I IFN induced by TDP-43 in induced pluripotent stem cell (iPSC)-derived motor neurons and in TDP-43 mutant mice. Finally, we document elevated levels of the specific cGAS signaling metabolite cGAMP in spinal cord samples from patients, which may be a biomarker of mtDNA release and cGAS/STING activation in ALS. Our results identify mtDNA release and cGAS/STING activation as critical determinants of TDP-43-associated pathology and demonstrate the potential for targeting this pathway in ALS.
DOI: 10.1016/j.cell.2020.09.020
Source: https://www.cell.com/cell/fulltext/S0092-8674(20)31161-2