Cargando…

Possible Role of Amyloidogenic Evolvability in Dementia with Lewy Bodies: Insights from Transgenic Mice Expressing P123H β-Synuclein

Dementia with Lewy bodies (DLB) is the second most prevalent neurodegenerative dementia after Alzheimer’s disease, and is pathologically characterized by formation of intracellular inclusions called Lewy bodies, the major constituent of which is aggregated α-synuclein (αS). Currently, neither a mech...

Descripción completa

Detalles Bibliográficos
Autores principales: Fujita, Masayo, Ho, Gilbert, Takamatsu, Yoshiki, Wada, Ryoko, Ikeda, Kazutaka, Hashimoto, Makoto
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215759/
https://www.ncbi.nlm.nih.gov/pubmed/32325870
http://dx.doi.org/10.3390/ijms21082849
_version_ 1783532262339379200
author Fujita, Masayo
Ho, Gilbert
Takamatsu, Yoshiki
Wada, Ryoko
Ikeda, Kazutaka
Hashimoto, Makoto
author_facet Fujita, Masayo
Ho, Gilbert
Takamatsu, Yoshiki
Wada, Ryoko
Ikeda, Kazutaka
Hashimoto, Makoto
author_sort Fujita, Masayo
collection PubMed
description Dementia with Lewy bodies (DLB) is the second most prevalent neurodegenerative dementia after Alzheimer’s disease, and is pathologically characterized by formation of intracellular inclusions called Lewy bodies, the major constituent of which is aggregated α-synuclein (αS). Currently, neither a mechanistic etiology nor an effective disease-modifying therapy for DLB has been established. Although two missense mutations of β-synuclein (βS), V70M and P123H, were identified in sporadic and familial DLB, respectively, the precise mechanisms through which βS mutations promote DLB pathogenesis remain elusive. To further clarify such mechanisms, we investigated transgenic (Tg) mice expressing P123H βS, which develop progressive neurodegeneration in the form of axonal swelling and non-motor behaviors, such as memory dysfunction and depression, which are more prominent than motor deficits. Furthermore, cross-breeding of P123H βS Tg mice with αS Tg mice worsened the neurodegenerative phenotype presumably through the pathological cross-seeding of P123H βS with αS. Collectively, we predict that βS misfolding due to gene mutations might be pathogenic. In this paper, we will discuss the possible involvement of amyloidogenic evolvability in the pathogenesis of DLB based on our previous papers regarding the P123H βS Tg mice. Given that stimulation of αS evolvability by P123H βS may underlie neuropathology in our mouse model, more radical disease-modifying therapy might be derived from the evolvability mechanism. Additionally, provided that altered βS were involved in the pathogenesis of sporadic DLB, the P123H βS Tg mice could be used for investigating the mechanism and therapy of DLB.
format Online
Article
Text
id pubmed-7215759
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-72157592020-05-22 Possible Role of Amyloidogenic Evolvability in Dementia with Lewy Bodies: Insights from Transgenic Mice Expressing P123H β-Synuclein Fujita, Masayo Ho, Gilbert Takamatsu, Yoshiki Wada, Ryoko Ikeda, Kazutaka Hashimoto, Makoto Int J Mol Sci Review Dementia with Lewy bodies (DLB) is the second most prevalent neurodegenerative dementia after Alzheimer’s disease, and is pathologically characterized by formation of intracellular inclusions called Lewy bodies, the major constituent of which is aggregated α-synuclein (αS). Currently, neither a mechanistic etiology nor an effective disease-modifying therapy for DLB has been established. Although two missense mutations of β-synuclein (βS), V70M and P123H, were identified in sporadic and familial DLB, respectively, the precise mechanisms through which βS mutations promote DLB pathogenesis remain elusive. To further clarify such mechanisms, we investigated transgenic (Tg) mice expressing P123H βS, which develop progressive neurodegeneration in the form of axonal swelling and non-motor behaviors, such as memory dysfunction and depression, which are more prominent than motor deficits. Furthermore, cross-breeding of P123H βS Tg mice with αS Tg mice worsened the neurodegenerative phenotype presumably through the pathological cross-seeding of P123H βS with αS. Collectively, we predict that βS misfolding due to gene mutations might be pathogenic. In this paper, we will discuss the possible involvement of amyloidogenic evolvability in the pathogenesis of DLB based on our previous papers regarding the P123H βS Tg mice. Given that stimulation of αS evolvability by P123H βS may underlie neuropathology in our mouse model, more radical disease-modifying therapy might be derived from the evolvability mechanism. Additionally, provided that altered βS were involved in the pathogenesis of sporadic DLB, the P123H βS Tg mice could be used for investigating the mechanism and therapy of DLB. MDPI 2020-04-19 /pmc/articles/PMC7215759/ /pubmed/32325870 http://dx.doi.org/10.3390/ijms21082849 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Fujita, Masayo
Ho, Gilbert
Takamatsu, Yoshiki
Wada, Ryoko
Ikeda, Kazutaka
Hashimoto, Makoto
Possible Role of Amyloidogenic Evolvability in Dementia with Lewy Bodies: Insights from Transgenic Mice Expressing P123H β-Synuclein
title Possible Role of Amyloidogenic Evolvability in Dementia with Lewy Bodies: Insights from Transgenic Mice Expressing P123H β-Synuclein
title_full Possible Role of Amyloidogenic Evolvability in Dementia with Lewy Bodies: Insights from Transgenic Mice Expressing P123H β-Synuclein
title_fullStr Possible Role of Amyloidogenic Evolvability in Dementia with Lewy Bodies: Insights from Transgenic Mice Expressing P123H β-Synuclein
title_full_unstemmed Possible Role of Amyloidogenic Evolvability in Dementia with Lewy Bodies: Insights from Transgenic Mice Expressing P123H β-Synuclein
title_short Possible Role of Amyloidogenic Evolvability in Dementia with Lewy Bodies: Insights from Transgenic Mice Expressing P123H β-Synuclein
title_sort possible role of amyloidogenic evolvability in dementia with lewy bodies: insights from transgenic mice expressing p123h β-synuclein
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215759/
https://www.ncbi.nlm.nih.gov/pubmed/32325870
http://dx.doi.org/10.3390/ijms21082849
work_keys_str_mv AT fujitamasayo possibleroleofamyloidogenicevolvabilityindementiawithlewybodiesinsightsfromtransgenicmiceexpressingp123hbsynuclein
AT hogilbert possibleroleofamyloidogenicevolvabilityindementiawithlewybodiesinsightsfromtransgenicmiceexpressingp123hbsynuclein
AT takamatsuyoshiki possibleroleofamyloidogenicevolvabilityindementiawithlewybodiesinsightsfromtransgenicmiceexpressingp123hbsynuclein
AT wadaryoko possibleroleofamyloidogenicevolvabilityindementiawithlewybodiesinsightsfromtransgenicmiceexpressingp123hbsynuclein
AT ikedakazutaka possibleroleofamyloidogenicevolvabilityindementiawithlewybodiesinsightsfromtransgenicmiceexpressingp123hbsynuclein
AT hashimotomakoto possibleroleofamyloidogenicevolvabilityindementiawithlewybodiesinsightsfromtransgenicmiceexpressingp123hbsynuclein