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Protection against Aβ-induced neuronal damage by KU-32: PDHK1 inhibition as important target
dc.contributor.author | Pal, Ranu | |
dc.contributor.author | Hui, Dongwei | |
dc.contributor.author | Menchen, Heather | |
dc.contributor.author | Zhao, Huiping | |
dc.contributor.author | Mozziconacci, Olivier | |
dc.contributor.author | Wilkins, Heather | |
dc.contributor.author | Blagg, Brian S. J. | |
dc.contributor.author | Schöneich, Christian | |
dc.contributor.author | Swerdlow, Russell H. | |
dc.contributor.author | Michaelis, Mary L. | |
dc.contributor.author | Michaelis, Elias K. | |
dc.date.accessioned | 2024-06-17T17:17:18Z | |
dc.date.available | 2024-06-17T17:17:18Z | |
dc.date.issued | 2023-11-14 | |
dc.identifier.citation | Pal R, Hui D, Menchen H, Zhao H, Mozziconacci O, Wilkins H, Blagg BSJ, Schöneich C, Swerdlow RH, Michaelis ML, Michaelis EK. Protection against Aβ-induced neuronal damage by KU-32: PDHK1 inhibition as important target. Front Aging Neurosci. 2023 Nov 14;15:1282855. doi: 10.3389/fnagi.2023.1282855. PMID: 38035268; PMCID: PMC10682733 | en_US |
dc.identifier.uri | https://hdl.handle.net/1808/35189 | |
dc.description.abstract | A feature of most neurodegenerative diseases is the presence of “mis-folded proteins” that form aggregates, suggesting suboptimal activity of neuronal molecular chaperones. Heat shock protein 90 (Hsp90) is the master regulator of cell responses to “proteotoxic” stresses. Some Hsp90 modulators activate cascades leading to upregulation of additional chaperones. Novobiocin is a modulator at the C-terminal ATP-binding site of Hsp90. Of several novobiocin analogs synthesized and tested for protection against amyloid beta (Aβ)-induced neuronal death, “KU-32” was the most potent in protecting primary neurons, but did not increase expression of other chaperones believed to help clear misfolded proteins. However, KU-32 reversed Aβ-induced superoxide formation, activated Complex I of the electron transfer chain in mitochondria, and blocked the Aβ-induced inhibition of Complex I in neuroblastoma cells. A mechanism for these effects of KU-32 on mitochondrial metabolism appeared to be the inhibition of pyruvate dehydrogenase kinase (PDHK), both in isolated brain mitochondria and in SH-SY5Y cells. PDHK inhibition by the classic enzyme inhibitor, dichloroacetate, led to neuroprotection from Aβ25-35-induced cell injury similarly to KU-32. Inhibition of PDHK in neurons would lead to activation of the PDH complex, increased acetyl-CoA generation, stimulation of the tricarboxylic acid cycle and Complex I in the electron transfer chain, and enhanced oxidative phosphorylation. A focus of future studies may be on the potential value of PDHK as a target in AD therapy. | en_US |
dc.publisher | Frontiers Media | en_US |
dc.rights | Copyright © 2023 Pal, Hui, Menchen, Zhao, Mozziconacci, Wilkins, Blagg, Schöneich, Swerdlow, Michaelis and Michaelis. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. | en_US |
dc.rights.uri | https://www.ncbi.nlm.nih.gov/pmc/about/copyright/ | en_US |
dc.subject | Novobiocin analog | en_US |
dc.subject | Superoxide | en_US |
dc.subject | Mitochondria | en_US |
dc.subject | Complex I | en_US |
dc.subject | Pyruvate dehydrogenase kinase | en_US |
dc.title | Protection against Aβ-induced neuronal damage by KU-32: PDHK1 inhibition as important target | en_US |
dc.type | Article | en_US |
kusw.kuauthor | Pal, Ranu | |
kusw.kuauthor | Hui, Dongwei | |
kusw.kuauthor | Menchen, Heather | |
kusw.kuauthor | Zhao, Huiping | |
kusw.kuauthor | Blagg, Brian S. J. | |
kusw.kuauthor | Schöneich, Christian | |
kusw.kuauthor | Michaelis, Mary L. | |
kusw.kuauthor | Michaelis, Elias K. | |
kusw.kudepartment | Department of Medicinal Chemistry | en_US |
kusw.kudepartment | Department of Pharmaceutical Chemistry | en_US |
kusw.kudepartment | Higuchi Biosciences Center | en_US |
dc.identifier.doi | 10.3389/fnagi.2023.1282855 | en_US |
kusw.oaversion | Scholarly/refereed, publisher version | en_US |
kusw.oapolicy | This item meets KU Open Access policy criteria. | en_US |
dc.identifier.pmid | PMC10682733 | en_US |
dc.rights.accessrights | openAccess | en_US |
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