Nature: Over the course of eight years, Yuan's team has provided a new direction for the treatment of neurodegenerative diseases in humans.

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 (ALS), have several important pathological characteristics: first, neuroinvestation mediated by small glial cells;
the current mainstream view that the above three factors are the important reasons for the occurrence and development of neurodegenerative diseases.
September 23, 2020, a team of fellow members of the American Academy of Sciences and Professor Yuan Yu of Harvard Medical School published a research paper in the journal Nature entitled: Modulating TRADD to restore cellular homeostasis and reseed apoptosis.
The study successfully screened the small molecular compound Apostatin-1, which inhibits both cell death and activates autophagy, and identified its target TRADD protein, further confirming that targeting TRADD is very safe, an eight-year effort that provides a new direction for treating neurodegenerative diseases in humans.
Current interventional research on neurodegenerative diseases mainly includes inhibition of neuroinflamm and cell death, and Yuan's team has worked over the past 20 years to establish the key role of RIPK1 in cell death and inflammatory response, and to develop INHIBIT1 inhibitors.
For example, aging-induced freezing disorder (ALS), protein kinase RIPK1-mediated inflammation of small glial cells, and death of less dendritic glial cells are previously found to be important causes of the disease (Xu, et al., 2018, Cell).
addition, in freezing disease (ALS) and Alzheimer's disease (AD), RIPK1-mediated neuroinstimation and cell death are involved in the progression of the disease (Ito, et al., 2016, Science; Ofengeim, et al., 2017, PNAS.).
So inhibiting kinase activity in RIPK1 is an important strategy for intervention in neurodegenerative diseases, and RIPK1 inhibitors are already conducting clinical trials of a variety of neurodegenerative diseases, including Alzheimer's disease (AD) and lyse (ALS).
, inhibition of RIPK1 does not solve the third problem of neurodegenerative diseases: the accumulation of pathological proteins caused by disorders of cell stability.
if only nerve inflammation and cell death were inhibited, cells in some diseases would probably not be able to restore internal stability, which would affect their normal functioning.
we know that activating autophagy pathways in cells restores cell stability and promotes the degradation of pathological protein aggregates.
but activating autophagy alone 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.
's team looked at the previous discovery process of RIPK1 and its inhibitor Nec-1 (Degterev et al. 2005, Nature Biolog Celly), using chemical genetics, using a composite high-volume screening model of small molecule compounds, to find small molecule compounds that inhibit both cell death and inflammation and activate autophagy, and then look further for small molecule targets.
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) to obtain a higher activity of small molecules, and named Apostatin-1.
team demonstrated through a large number of cell biology experiments and biochemistry experiments that Apostatin-1's target is a bridging protein called TRADD.
through in vitro and in vivo experiments, the team confirmed that targeted TRADD can achieve both of these goals, namely, inhibiting RIPK1 activation, and activating autophagy recovery cell stability and removing pathological protein aggregates.
mice that had been knocked out by the TRADD gene were 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 it would be very safe to target TRADD, an eight-year effort that provides a new direction for treating neurodegenerative diseases in humans.
Yuan Yuying, a professor at Harvard Medical School and a member of the National Academy of Sciences, was admitted to Fudan University in 1977 in his first year of reinstateing the college entrance examination and received his Ph.D. in Neuroscience from Harvard University in 1989.
associate professor at Harvard Medical School in 1992 and a lifelong professor at Harvard Medical School in 2000.
Academy of Arts and Sciences in 2007 and the National Academy of Sciences in 2017.
his time at Harvard, Mr. Yuan learned from Robert Horwitz (H. Professor Robert Horvitz, Yuan Yuying, identified the ced-3 and ced-4 proteins as the driving force behind the death of the programed cells of the beautiful crypto-worm, and later identified the mammalian homogen of ced-3, also known as caspase-1.
made an important contribution to her mentor Robert Horwitz winning the Nobel Prize in Chemistry.
2005, Yuan's team discovered a non-apoptosis cell procedural death, necroptosis.
RIPK1 inhibitors developed on this basis have been conducted in clinical trials for neurodegenerative diseases such as freezing disease, Alzheimer's disease and inflammatory diseases such as rheumatoid arthritis, psoriasis and Crohn's disease.
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