Exploration of Aberrant E3 Ligases Implicated in Alzheimer’s Disease and Development of Chemical Tools to Modulate Their Function

The Ubiquitin Proteasome System (UPS) is responsible for the degradation of misfolded or aggregated proteins via a multistep ATP-dependent proteolytic mechanism. This process involves a cascade of ubiquitin (Ub) transfer steps from E1 to E2 to E3 ligase. The E3 ligase transfers Ub to a targeted prot...

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Autores principales:	Frances M. Potjewyd, Alison D. Axtman
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	Alzheimer’s disease neurodegeneration E3 ligase chemical tools structures ubiquitination Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/2a5a5ba009cb40a5ab39036ae96559bb
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spelling	oai:doaj.org-article:2a5a5ba009cb40a5ab39036ae96559bb2021-11-18T09:16:43ZExploration of Aberrant E3 Ligases Implicated in Alzheimer’s Disease and Development of Chemical Tools to Modulate Their Function1662-510210.3389/fncel.2021.768655https://doaj.org/article/2a5a5ba009cb40a5ab39036ae96559bb2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fncel.2021.768655/fullhttps://doaj.org/toc/1662-5102The Ubiquitin Proteasome System (UPS) is responsible for the degradation of misfolded or aggregated proteins via a multistep ATP-dependent proteolytic mechanism. This process involves a cascade of ubiquitin (Ub) transfer steps from E1 to E2 to E3 ligase. The E3 ligase transfers Ub to a targeted protein that is brought to the proteasome for degradation. The inability of the UPS to remove misfolded or aggregated proteins due to UPS dysfunction is commonly observed in neurodegenerative diseases, such as Alzheimer’s disease (AD). UPS dysfunction in AD drives disease pathology and is associated with the common hallmarks such as amyloid-β (Aβ) accumulation and tau hyperphosphorylation, among others. E3 ligases are key members of the UPS machinery and dysfunction or changes in their expression can propagate other aberrant processes that accelerate AD pathology. The upregulation or downregulation of expression or activity of E3 ligases responsible for these processes results in changes in protein levels of E3 ligase substrates, many of which represent key proteins that propagate AD. A powerful way to better characterize UPS dysfunction in AD and the role of individual E3 ligases is via the use of high-quality chemical tools that bind and modulate specific E3 ligases. Furthermore, through combining gene editing with recent advances in 3D cell culture, in vitro modeling of AD in a dish has become more relevant and possible. These cell-based models of AD allow for study of specific pathways and mechanisms as well as characterization of the role E3 ligases play in driving AD. In this review, we outline the key mechanisms of UPS dysregulation linked to E3 ligases in AD and highlight the currently available chemical modulators. We present several key approaches for E3 ligase ligand discovery being employed with respect to distinct classes of E3 ligases. Where possible, specific examples of the use of cultured neurons to delineate E3 ligase biology have been captured. Finally, utilizing the available ligands for E3 ligases in the design of proteolysis targeting chimeras (PROTACs) to degrade aberrant proteins is a novel strategy for AD, and we explore the prospects of PROTACs as AD therapeutics.Frances M. PotjewydAlison D. AxtmanFrontiers Media S.A.articleAlzheimer’s diseaseneurodegenerationE3 ligasechemical toolsstructuresubiquitinationNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENFrontiers in Cellular Neuroscience, Vol 15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Alzheimer’s disease neurodegeneration E3 ligase chemical tools structures ubiquitination Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	Alzheimer’s disease neurodegeneration E3 ligase chemical tools structures ubiquitination Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Frances M. Potjewyd Alison D. Axtman Exploration of Aberrant E3 Ligases Implicated in Alzheimer’s Disease and Development of Chemical Tools to Modulate Their Function
description	The Ubiquitin Proteasome System (UPS) is responsible for the degradation of misfolded or aggregated proteins via a multistep ATP-dependent proteolytic mechanism. This process involves a cascade of ubiquitin (Ub) transfer steps from E1 to E2 to E3 ligase. The E3 ligase transfers Ub to a targeted protein that is brought to the proteasome for degradation. The inability of the UPS to remove misfolded or aggregated proteins due to UPS dysfunction is commonly observed in neurodegenerative diseases, such as Alzheimer’s disease (AD). UPS dysfunction in AD drives disease pathology and is associated with the common hallmarks such as amyloid-β (Aβ) accumulation and tau hyperphosphorylation, among others. E3 ligases are key members of the UPS machinery and dysfunction or changes in their expression can propagate other aberrant processes that accelerate AD pathology. The upregulation or downregulation of expression or activity of E3 ligases responsible for these processes results in changes in protein levels of E3 ligase substrates, many of which represent key proteins that propagate AD. A powerful way to better characterize UPS dysfunction in AD and the role of individual E3 ligases is via the use of high-quality chemical tools that bind and modulate specific E3 ligases. Furthermore, through combining gene editing with recent advances in 3D cell culture, in vitro modeling of AD in a dish has become more relevant and possible. These cell-based models of AD allow for study of specific pathways and mechanisms as well as characterization of the role E3 ligases play in driving AD. In this review, we outline the key mechanisms of UPS dysregulation linked to E3 ligases in AD and highlight the currently available chemical modulators. We present several key approaches for E3 ligase ligand discovery being employed with respect to distinct classes of E3 ligases. Where possible, specific examples of the use of cultured neurons to delineate E3 ligase biology have been captured. Finally, utilizing the available ligands for E3 ligases in the design of proteolysis targeting chimeras (PROTACs) to degrade aberrant proteins is a novel strategy for AD, and we explore the prospects of PROTACs as AD therapeutics.
format	article
author	Frances M. Potjewyd Alison D. Axtman
author_facet	Frances M. Potjewyd Alison D. Axtman
author_sort	Frances M. Potjewyd
title	Exploration of Aberrant E3 Ligases Implicated in Alzheimer’s Disease and Development of Chemical Tools to Modulate Their Function
title_short	Exploration of Aberrant E3 Ligases Implicated in Alzheimer’s Disease and Development of Chemical Tools to Modulate Their Function
title_full	Exploration of Aberrant E3 Ligases Implicated in Alzheimer’s Disease and Development of Chemical Tools to Modulate Their Function
title_fullStr	Exploration of Aberrant E3 Ligases Implicated in Alzheimer’s Disease and Development of Chemical Tools to Modulate Their Function
title_full_unstemmed	Exploration of Aberrant E3 Ligases Implicated in Alzheimer’s Disease and Development of Chemical Tools to Modulate Their Function
title_sort	exploration of aberrant e3 ligases implicated in alzheimer’s disease and development of chemical tools to modulate their function
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/2a5a5ba009cb40a5ab39036ae96559bb
work_keys_str_mv	AT francesmpotjewyd explorationofaberrante3ligasesimplicatedinalzheimersdiseaseanddevelopmentofchemicaltoolstomodulatetheirfunction AT alisondaxtman explorationofaberrante3ligasesimplicatedinalzheimersdiseaseanddevelopmentofchemicaltoolstomodulatetheirfunction
_version_	1718420892349890560

Exploration of Aberrant E3 Ligases Implicated in Alzheimer’s Disease and Development of Chemical Tools to Modulate Their Function

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