Hrd1 Facilitates Tau Degradation and Promotes Neuron Survival

Abstract

Intraneuronal accumulation of abnormal phosphorylated tau (p-tau) is a molecular pathology in many neurodegenerative tauopathies, including Alzheimer's disease (AD) and frontotemporal dementia with parkinsonism-linked to chromosome 17 (FTDP-17). However, the underlying mechanism remains unclear. Here, we showed an inverse relationship between endoplasmic reticulum membrane ubiquitin ligase (E3) Hrd1 expression and p-tau accumulation in the hippocampal neurons of AD, and proposed that Hrd1 may be a negative regulator of p-tau. This notion was further supported by in vitro study demonstrating that Hrd1 interacted with tau and promoted the degradation of total tau and p-tau as well. The degradation of tau depended on its Hrd1 E3 activity. Knockdown of endogenous Hrd1 with siRNA stabilized tau levels. In addition, inhibition of proteasome maintained tau level and increased Hrd1-mediated tau ubiquitination, suggesting the proteasome was involved in tau/p-tau degradation. Over-expression of Hrd1 significantly alleviated tau cytotoxicity and promoted cell survival. These results indicated that Hrd1 functions as an E3 targeting tau or abnormal p-tau for proteasome degradation. The study provides an important insight into the molecular mechanisms of human tauopathies.

Activator protein‑1 is a novel regulator of mesencephalic astrocyte‑derived neurotrophic factor transcription

“…Further studies have suggested that MANF protects against various forms of ER stress-induced cell damage via its C-terminal domain. Our previous studies also confirmed that MANF protects neurons in rats with middle cerebral artery occlusion-induced focal cerebral ischemia via alleviating ER stress (5,7,16,17). A recent study identified MANF as an immune modulator that serves a critical role in mediating tissue repair in the retina (18).…”

Effects of Oxidative Stress on the Solubility of HRD1, a Ubiquitin Ligase Implicated in Alzheimer’s Disease

“…In addition, hyperphosphorylation of tau accumulated in the cerebral cortex of JNPL3 mice is at a low level. Regarding the interaction between HRD1 and p-tau [35], we believe that hyperphosphorylated tau is likely to lead to HRD1 accumulation and/or insolubility.…”

“…Ubiquitination of tau and phosphorylated tau (p-tau) by HRD1 targets these proteins for degradation by the proteasome [35]. Tau phosphorylation is mainly due to glycogen synthase kinase-3β (GSK-3β) [36], which is activated in relation to ER stress and the ER-associated chaperone Bip, also known as GRP78 [37].…”

Ubiquitin ligase SYVN1/HRD1 facilitates degradation of the SERPINA1 Z variant/α-1-antitrypsin Z variant via SQSTM1/p62-dependent selective autophagy

“…pcDNA3.1/myc-His-SYVN1 (wild type), pcDNA3.1/myc-His-SYVN1C1A, pCIneo-SYVN1-FLAG, pcDNA3.1/Zeo(+)-SERPINA1 E342K /ATZ and pcDNA3.1/Zeo(+)-SERPINA1 plasmids have been described previously 26, 29 . Plasmids pRK5-HA-ubiquitin-WT, pRK5-HA-ubiquitin-K48, pRK5-HA-ubiquitin-K63, pRK5-HA-ubiquitin-K48R, pRK5-HA-ubiquitin-K63R, and pRK5-FLAG-USP2A were kindly provided by Professor Ronggui Hu at the Chinese Academy of Sciences 52 and Professor Hongbin Shu at Wuhan University (China) 63, 64 .…”

“…Double immunofluorescent labeling was performed with according primary antibodies and fluorescence labeled second antibodies, respectively, using a previously published method 26 . Confocal images were captured using a confocal microscope (LSM710, Carl Zeiss, Tokyo, Japan) with ZEISS ZEN Imaging Software.…”