Research Paper Volume 13, Issue 13 pp 17097—17117
Inhibition of heat shock proteins increases autophagosome formation, and reduces the expression of APP, Tau, SOD1 G93A and TDP-43
- 1 Department of Biochemistry and Molecular Biology, Richmond, VA 23298, USA
- 2 Department of Pharmacology and Toxicology, Richmond, VA 23298, USA
- 3 Department of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA
- 4 Translational Genomics Research Institute (TGEN), Phoenix, AZ 85004, USA
- 5 Banner Alzheimer’s Institute, Phoenix, AZ 85006, USA
Received: March 30, 2021 Accepted: July 2, 2021 Published: July 12, 2021https://doi.org/10.18632/aging.203297
How to Cite
Copyright: © 2021 Dent et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Aberrant expression and denaturation of Tau, amyloid-beta and TDP-43 can lead to cell death and is a major component of pathologies such as Alzheimer’s Disease (AD). AD neurons exhibit a reduced ability to form autophagosomes and degrade proteins via autophagy. Using genetically manipulated colon cancer cells we determined whether drugs that directly inhibit the chaperone ATPase activity or cause chaperone degradation and endoplasmic reticulum stress signaling leading to macroautophagy could reduce the levels of these proteins. The antiviral chaperone ATPase inhibitor AR12 reduced the ATPase activities and total expression of GRP78, HSP90, and HSP70, and of Tau, Tau 301L, APP, APP692, APP715, SOD1 G93A and TDP-43. In parallel, it increased the phosphorylation of ATG13 S318 and eIF2A S51 and caused eIF2A-dependent autophagosome formation and autophagic flux. Knock down of Beclin1 or ATG5 prevented chaperone, APP and Tau degradation. Neratinib, used to treat HER2+ breast cancer, reduced chaperone levels and expression of Tau and APP via macroautophagy, and neratinib interacted with AR12 to cause further reductions in protein levels. The autophagy-regulatory protein ATG16L1 is expressed as two isoforms, T300 or A300: Africans trend to express T300 and Europeans A300. We observed higher basal expression of Tau in T300 cells when compared to isogenic A300 cells. ATG16L1 isoform expression did not alter basal levels of HSP90, HSP70 or HSP27, however, basal levels of GRP78 were reduced in A300 cells. The abilities of both AR12 and neratinib to stimulate ATG13 S318 and eIF2A S51 phosphorylation and autophagic flux was also reduced in A300 cells. Our data support further evaluation of AR12 and neratinib in neuronal cells as repurposed treatments for AD.
ER: endoplasmic reticulum; AIF: apoptosis inducing factor; AMPK: AMP-dependent protein kinase; mTOR: mammalian target of rapamycin; MAPK: mitogen activated protein kinase; CMV: empty vector plasmid or virus; si: small interfering; SCR: scrambled; VEH: vehicle; FTY: FTY720, fingolimod; DMF: dimethyl fumarate; MMF: monomethyl fumarate; NER: neratinib; AD: Alzheimer’s Disease; ALS: amyotrophic lateral sclerosis; HC: Huntington’s Chorea.