Essential role of POLDIP2 in Tau aggregation and neurotoxicity via autophagy/proteasome inhibition.
In Alzheimer's disease and other tauopathy, abnormal Tau proteins form intracellular aggregates and Tau filaments. However, the mechanisms that regulate Tau aggregation are not fully understood. In this paper, we show that POLDIP2 is a novel regulator of Tau aggregation. From a cell-based screening using cDNA expression library, we isolated POLDIP2 which increased Tau aggregation. Expression of POLDIP2 was increased in neuronal cells by the multiple stresses, including Aβ, TNF-α and H2O2. Accordingly, ectopic expression of POLDIP2 enhanced the formation of Tau aggregates without affecting Tau phosphorylation, while down-regulation of POLDIP2 alleviated ROS-induced Tau aggregation. Interestingly, we found that POLDIP2 overexpression induced impairments of autophagy activity and partially proteasome activity and this activities were retained in DUF525 domain of POLDIP2. In a drosophila model of human tauopathy, knockdown of the drosophila POLDIP2 homolog, CG12162, attenuated rough eye phenotype induced by Tau overexpression. Further, the lifespan of neural-Tau(R406W) transgenic files were recovered by CG12162 knockdown. Together, these observations indicate that POLDIP2 plays a crucial role in Tau aggregation via the impairment of autophagy activity, providing insight into Tau aggregation in Tau pathology.
Global Research Laboratory, School of Biological Sciences, Seoul National University, Seoul 151-747, Republic of Korea.
YoungDoo
Y
Kim
Global Research Laboratory, School of Biological Sciences, Seoul National University, Seoul 151-747, Republic of Korea.
Hyejin
H
Park
Global Research Laboratory, School of Biological Sciences, Seoul National University, Seoul 151-747, Republic of Korea.
Jihoon
J
Nah
Global Research Laboratory, School of Biological Sciences, Seoul National University, Seoul 151-747, Republic of Korea.
Seowon
S
Moon
Global Research Laboratory, School of Biological Sciences, Seoul National University, Seoul 151-747, Republic of Korea.
WonJae
W
Lee
Global Research Laboratory, School of Biological Sciences, Seoul National University, Seoul 151-747, Republic of Korea.
Se-Hoon
SH
Hong
Global Research Laboratory, School of Biological Sciences, Seoul National University, Seoul 151-747, Republic of Korea.
Tae-In
TI
Kam
Global Research Laboratory, School of Biological Sciences, Seoul National University, Seoul 151-747, Republic of Korea. Electronic address: ykjung@snu.ac.kr.
Yong-Keun
YK
Jung
D000818:Animals; D030801:Animals, Genetically Modified; D001343:Autophagy; D002460:Cell Line; D004195:Disease Models, Animal; D015536:Down-Regulation; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D017344:Genes, Insect; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D029721:Drosophila Proteins; C054369:MAPT protein, human; D009687:Nuclear Proteins; C473592:POLDIP2 protein, human; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D016875:tau Proteins; D046988:Proteasome Endopeptidase Complex
Autophagy; Lifespan; POLDIP2; Proteasome; Tau