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Biochem Biophys Res Commun. 2015 Jun 26;462(2):112-8. doi: 10.1016/j.bbrc.2015.04.084. Epub 2015 Apr 27.

Essential role of POLDIP2 in Tau aggregation and neurotoxicity via autophagy/proteasome inhibition.

Author information

1
Global Research Laboratory, School of Biological Sciences, Seoul National University, Seoul 151-747, Republic of Korea.
2
Global Research Laboratory, School of Biological Sciences, Seoul National University, Seoul 151-747, Republic of Korea. Electronic address: ykjung@snu.ac.kr.

Abstract

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.

KEYWORDS:

Autophagy; Lifespan; POLDIP2; Proteasome; Tau

PMID:
25930997
DOI:
10.1016/j.bbrc.2015.04.084
[Indexed for MEDLINE]

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