Junying Yuan, Ph.D.

Harvard Medical School Department of Cell Biology

Junying Yuan, Ph.D.

Harvard Medical School Department of Cell Biology

Biography

Junying Yuan received her Ph.D. in Neuroscience from Harvard University in 1989 and her undergraduate degree from Fudan University, Shanghai, China, in 1982. Dr. Yuan carried out her Ph.D. thesis work at the Massachusetts Institute of Technology in the laboratory of H. R. Horvitz. She was first appointed as Assistant Professor at Harvard Medical School in 1992, when she became a Principal Investigator of the Cardiovascular Research Center at Massachusetts General Hospital. She joined the Department of Cell Biology in 1996 and was appointed a Professor of Cell Biology at Harvard Medical School in 2000. In 2014, Dr. Yuan was appointed as Elizabeth D. Hay Professor of Cell Biology, a Professorship that honors the late Professor Elizabeth D. Hay, the first female full professor in the history of Harvard Medical School.

Dr. Yuan is a pioneer and a leader in the cell death field. Dr. Yuan made transformative discoveries on two distinct forms of cell death, apoptosis and necroptosis in mammalian cells. Her discovery of mammalian caspases led to a molecular era in apoptosis research. Her development of necrostatins demonstrated the existence and significance of a regulated necrosis mechanism, termed necroptosis, in human degenerative diseases. Dr. Yuan’s accomplishments have been honored by many awards including the Innovator Award for Breast Cancer Research and NIH Director’s Pioneer award. She is a fellow of the American Academy of Arts and Sciences, a fellow of the American Association for the Advancement of Sciences and a member of the National Academy of Sciences (US).

Regulation of RIPK1 activation in neurodegenerative diseases associated with aging

Upregulation of death receptor family ligands, such as TNFα, can sensitize cells in the CNS to apoptosis and a form of regulated necrotic cell death known as necroptosis that is mediated by RIPK1, RIPK3 and MLKL. Necroptosis promotes cell death and neuroinflammation to mediate pathogenesis in multiple neurodegenerative diseases, including multiple sclerosis, amyotrophic lateral sclerosis, Parkinson’s disease and Alzheimer’s disease. RIPK1 kinase activity is suppressed by inhibitory phosphorylations mediated directly by TAK1 and by the kinases activated by TAK1, including MK2 and IKKs, and TBK1.

Aging is a major risk factor for both genetic and sporadic neurodegenerative disorders. However, it is unclear how aging interacts with genetic predispositions to promote neurodegeneration. We investigated how partial loss-of-function of TBK1, a major genetic cause for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) comorbidity, leads to age-dependent neurodegeneration. We show that TBK1 is an endogenous inhibitor of RIPK1 and the embryonic lethality of Tbk1-/- mice is dependent on RIPK1 kinase activity. In aging human brains, another endogenous RIPK1 inhibitor, TAK1, exhibits a marked decrease in expression. We show that in Tbk1+/- mice, the reduced myeloid TAK1 expression promotes all the key hallmarks of ALS/FTD, including neuroinflammation, TDP-43 aggregation, axonal degeneration, neuronal loss and behavior deficits, which are blocked upon inhibition of RIPK1. Thus, aging facilitates RIPK1 activation by reducing TAK1 expression, which cooperates with genetic risk factors to promote the onset of ALS/FTD.

References:

Xu D, Jin T, Zhu H, Chen H, Ofengeim D, Zou C, Mifflin L, Pan L, Amin P, Li W, Shan B, Naito MG, Meng H, Li Y, Pan H, Aron L, Adiconis X, Levin JZ, Yankner BA, Yuan J. TBK1 Suppresses RIPK1-Driven Apoptosis and Inflammation during Development and in Aging. Cell. 2018. 174(6):1477-1491.

Geng J, Ito Y, Shi L, Amin P, Chu J, Ouchida AT, Mookhtiar AK, Zhao H, Xu D, Shan B, Najafov A, Gao G, Akira S, Yuan J. Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis. Nat Commun. 2017 Aug 25;8(1):359. doi: 10.1038/s41467-017-00406-w. PubMed PMID: 28842570; PubMed Central PMCID: PMC5572456.

All sessions by Junying Yuan, Ph.D.