The Roles Of Alterations Of SIRT3 And Its Substrates' Acetylation In Pathogenic Mechanism Of Prion Diseases

Prion diseases are a series of lethal neurodegenerative diseases in humans and animals.The neuropathologic changes are characterized by neuronal loss,spongiform degeneration,astrogliosis and PrPSc aggregation in the central nervous system(CNS).Mitochondrial dysfunction and oxidative stress are closely linked to the pathogenesis of aging-associated neurodegenerative diseases,including prion diseases.SIRT3 is the major mitochondria NAD+ dependent deacetylase that acts as a key regulator of mitochondrial protein function.Although SIRT3 was reported to be linked to pathogenesis of several neurodegenerative diseases,there is no evidence for the involvement of SIRT3 in prion diseases.In this study,we have demonstrated a declined status of SIRT3 both in the levels of cultured cells and experimental rodent model during scrapie prion replication and infection Such decreased SIRT3 activity led to a decreased deacetylating activity.We have found that SOD2,one of the substrates of SIRT3,is hyperacetylated at Lysine 68 and 122 in SMB-S15 cells and in the brains of SMB-S15 infected mice,which resulted declined SOD2 activity,and such declined SOD2 activities subsequently caused increase of intracellular ROS.Mitochondrial ATP5? is another substrate of SIRT3,whose hyperacetylation can decrease intracellular ATP levels by regulating the activity of ATP synthase.We have presented that the acetylated form of ATP5? is increased in SMB-S15 cells,which resulted decreased intracellular ATP level.On the other hand,we have also proposed the evidences that removal of prion propagation in the cultured cells by resveratrol partially recovers the cellular SIRT3 activity.Those data highlight a close linkage between the prion replication and mitochondrial deacetylation due to SIRT3,thereby partially explaining mitochondrial dysfunction in prion diseases.