Scientists have found that targeting TRADD restores cell stability and inhibits apoptosis at the same time

neurodegenerative disease is a major disease affecting human health, but there are no effective interventions. Neurodegenerative diseases (NDs), such as Alzheimer's disease (AD) and freezing disease (ALS), have several important pathological characteristics: first, neuroinvestation mediated by small glial cells; At present, the mainstream view holds that the above three factors are the important reasons for the occurrence and development of ND.
, at 23:00 BST on September 23, 2020, the Research Group of Yuan Yu of Harvard Medical School published a research paper entitled "Modulating TRADD to restore cellular homeostasis and respoptosis" in the journal Nature, which regulates the TRADD protein to restore intracerticosis and inhibits apoptosis at the same time.
current interventional research on ND mainly includes inhibition of neuroinflamm and cell death, and the team's work over the past 20 years has established the key role of RIPK1 in cell death and inflammatory response, and developed RIPK1 inhibitors. For example, it has previously been found that aging-induced freezing disorder (ALS), protein kinase RIPK1-mediated inflammation of small glial cells, and death of less dendritic glial cells are important causes of the disease (Xu, et al., 2018, Cell). In addition, in ALS and AD with OPTN mutations, RIPK1-mediated neuro-inflammation and cell death are involved in the progression of the disease (Ito, et al., 2016, ScienceDaily; Ofengeim, et al.,2017, PNAS.)。 Therefore, inhibiting the kinase activity of RIPK1 is an important intervention strategy for ND, and RIPK1 inhibitors are already conducting a variety of ND clinical trials, including AD and ALS.
, inhibition of RIPK1 does not solve the third problem of ND: the accumulation of pathological proteins caused by the disorder of cell stability. If only nerve inflammation and cell death are inhibited, cells in some diseases are likely to have no way to restore internal stability, which can affect their normal functioning. And we know that activating autophagy in cells restores cell stability and promotes the degradation of pathological protein aggregates. But simply activating autophagy does not inhibit nerve inflammation and cell death.
these considerations, a new strategy is needed to suppress cell death and inflammation and activate autophagy at the same time. They referred to the previous discovery process of RIPK1 and its inhibitor Nec-1 (Degterev et al. In 2005, Nature Cell Biology, using chemical genetics, used a composite high-volume screening model of small molecule compounds to find small molecular compounds that inhibit both cell death and inflammation and activate autophagy, and then further look for targets for small molecules.
team used the cell death model and cell autophagy model dependent on RIPK1, and conducted multiple rounds of screening from 170,000 compounds, and finally found small molecules (ICCB-17 and ICCB-19) that met the above requirements. Further, through structural modification (SAR), a small molecule with higher activity is obtained and named Apostatin-1. Through a large number of cell biology experiments and biochemistry experiments, the team demonstrated that the target of Apostatin-1 is a bridging protein called TRADD. It has been proved in vitro and in vivo that targeted TRADD can achieve the above two objectives, namely, inhibiting the activation of RIPK1, and activating autophagy recovery cell stability and removing pathological protein aggregates.。 Mice with the TRADD gene knock-out have been shown to be not only completely healthy, but also resistant to tumor necrotic cause TNF alpha and lipid polysaccharid LPS-induced systemic inflammatory syndrome (SIRS) and death, so targeting TRADD will be very safe. The eight-year effort offers new directions for the treatment of neurodegenerative diseases in humans. (Source: Science Network)
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