时间：10月23日（下周二）上午10:00

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. Here we investigate 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.