Tau Clearance Mechanisms

Tang, Maoping; Harrison, Jarreau; Deaton, Carol A.; Johnson, Gail V.W.

doi:10.1007/978-981-32-9358-8_5

Cited by 20 publications

(19 citation statements)

References 84 publications

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“…The co-chaperone BAG3 has been shown to facilitate the degradation of Tau and APP [24][25][26]. Overexpression of GRP78, HSP70 or HSP90, or knock down of GRP78, HSP70 or HSP90 surprisingly did not signi cantly alter the basal expression level of BAG3 (data not shown).…”

Section: Resultsmentioning

confidence: 90%

“…Chaperones in cells are complexed with other proteins including BAG3 (associated with HSP70) and AHA1 and CDC37 (associated with HSP90). BAG3, AHA1 and CDC37 have all been linked to AD pathology [24][25][26][27][28][29][30]. BAG3 has been shown to enhance Tau degradation by autophagy [22][23][24].…”

Section: Resultsmentioning

confidence: 99%

“…The co-chaperone BAG3 has been linked to the regulation of autophagy and cell viability, for example, Ji et al demonstrated that BAG3 facilitates the autophagic degradation of Tau [24][25][26]. AR12 increased BAG3 expression and knock down of BAG3 reduced the ability of AR12 to cause autophagosome formation.…”

Section: Signaling By Erbb2 and Kras Play Important Roles In The Deve...mentioning

confidence: 99%

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AR12 increases BAG3 expression via ER stress signaling which is essential for Tau and APP degradation via LC3-associated phagocytosis and macroautophagy

Dent

Booth

Roberts

et al. 2022

Preprint

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Background We defined the mechanisms by which the chaperone ATPase inhibitor AR12 and the multi-kinase inhibitor neratinib interacted to reduce expression of Tau and amyloid-precursor protein (APP) in microglia and neuronal cells. Methods In vitro cell culture; in-cell immunostaining using a Hermes wide-field microscope with densitometric imaging software; transfection of siRNA and plasmids; assessments of autophagy using a plasmid to express LC3-GFP-RFP. Results AR12 and neratinib interacted to increase the phosphorylation of eIF2A S51 and the expression of BAG3, Beclin1 and ATG5, and in parallel, enhanced autophagosome formation and autophagic flux. Knock down of BAG3, Beclin1 or ATG5 abolished autophagosome formation and significantly reduced degradation of p62, LAMP2, Tau, APP, and GRP78 (total and plasma membrane). Knock down of Rubicon, a key component of LC3-associated phagocytosis (LAP), significantly reduced autophagosome formation but not autophagic flux and prevented degradation of Tau, APP, and cell surface GRP78, but not ER-localized GRP78. Knock down of Beclin1, ATG5 or Rubicon or over-expression of GRP78 prevented the significant increase in eIF2A phosphorylation. Knock down of eIF2A prevented the increase in BAG3 expression and significantly reduced autophagosome formation, autophagic flux, and it prevented Tau and APP degradation. Conclusions We conclude that AR12 has the potential to reduce Tau and APP levels in neurons and microglia via the actions of LAP, endoplasmic reticulum stress signaling and macroautophagy. We hypothesize that the initial inactivation of GRP78 catalytic function by AR12 facilitates an initial increase in eIF2A phosphorylation which in turn is essential for greater levels of eIF2A phosphorylation, greater levels of BAG3 and macroautophagy and eventually leading to significant amounts of APP/Tau degradation.

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Section: Resultsmentioning

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Signaling By Erbb2 and Kras Play Important Roles In The Deve...mentioning

confidence: 99%

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AR12 increases BAG3 expression via ER stress signaling which is essential for Tau and APP degradation via LC3-associated phagocytosis and macroautophagy

Dent

Booth

Roberts

et al. 2022

Preprint

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“…This finding agrees with previous papers that have also used genetic inactivation of USP14 to question the role of USP14 in directly regulating the turnover of aggregate‐prone proteins and found that there was no detectable change in the level of MAPT in both cell and animal models deficient for USP14 (Jin et al., 2012; Ortuno et al, 2016). While evidence exists that MAPT can be a substrate for the proteasome (Babu et al., 2005; Choi et al., 2016; Chu et al., 2016; Han et al., 2014; Petrucelli et al., 2004), other studies have suggested that MAPT turnover can also occur through a proteasome‐independent pathway (Brown et al., 2005; Feuillette et al., 2005; Lee et al., 2013), such as the autophagic pathway (Dolan & Johnson, 2010; Hamano et al., 2008; Jimenez‐Sanchez et al., 2012; Tang et al., 2019). Therefore, MAPT degradation likely occurs through both the proteasome and autophagy pathways, and the decision to utilize these pathways may reflect either constitutive or stress‐induced MAPT degradation (Lee et al., 2013).…”

Section: Discussionmentioning

confidence: 99%

“…While evidence exists that MAPT can be a substrate for the proteasome (Babu et al, 2005;Choi et al, 2016;Chu et al, 2016;Han et al, 2014;Petrucelli et al, 2004), other studies have suggested that MAPT turnover can also occur through a proteasome-independent pathway (Brown et al, 2005;Feuillette et al, 2005;Lee et al, 2013), such as the autophagic pathway (Dolan & Johnson, 2010;Hamano et al, 2008;Jimenez-Sanchez et al, 2012;Tang et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Examination of genetic and pharmacological tools to study the proteasomal deubiquitinating enzyme ubiquitin‐specific protease 14 in the nervous system

Tian

McLean

Wilson

et al. 2020

Journal of Neurochemistry

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Strategies for enhancing protein degradation have been proposed for treating neurological diseases associated with a decline in proteasome activity. A proteasomal deubiquitinating enzyme that controls substrate entry into proteasomes, ubiquitin‐specific protease 14 (USP14), is an attractive candidate for therapies that modulate proteasome activity. This report tests the validity of genetic and pharmacological tools to study USP14’s role in regulating protein abundance. Although previous studies implicated USP14 in the degradation of microtubule associate protein tau, tar DNA binding protein, and prion protein, the levels of these proteins were similar in our neurons cultured from wild type and USP14‐deficient mice. Neither loss nor over‐expression of USP14 affected the levels of these proteins in mice, implying that modifying the amount of USP14 is not sufficient to alter their steady‐state levels. However, neuronal over‐expression of a catalytic mutant of USP14 showed that manipulating USP14’s ubiquitin‐hydrolase activity altered the levels of specific proteins in vivo. Although pharmacological inhibitors of USP14’s ubiquitin‐hydrolase activity reduced microtubule associate protein tau, tar DNA binding protein, and prion protein in culture, the effect was similar in wild type and USP14‐deficient neurons, thus impacting their use for specifically evaluating USP14 in a therapeutic manner. While examining how targeting USP14 may affect other proteins in vivo, this report showed that fatty acid synthase, v‐rel reticuloendotheliosis viral oncogene homolog, CTNNB1, and synaptosome associated protein 23 are reduced in USP14‐deficient mice; however, loss of USP14 differentially altered the levels of these proteins in the liver and brain. As such, it is critical to more thoroughly examine how inhibiting USP14 alters protein abundance to determine if targeting USP14 will be a beneficial strategy for treating neurodegenerative diseases.

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Activity-dependent tau cleavage by caspase-3 promotes neuronal dysfunction and synaptotoxicity

et al. 2023

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Tau Clearance Mechanisms

Cited by 20 publications

References 84 publications

AR12 increases BAG3 expression via ER stress signaling which is essential for Tau and APP degradation via LC3-associated phagocytosis and macroautophagy

AR12 increases BAG3 expression via ER stress signaling which is essential for Tau and APP degradation via LC3-associated phagocytosis and macroautophagy

Examination of genetic and pharmacological tools to study the proteasomal deubiquitinating enzyme ubiquitin‐specific protease 14 in the nervous system

Activity-dependent tau cleavage by caspase-3 promotes neuronal dysfunction and synaptotoxicity

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