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.
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.