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...
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doaj-1b52aa55fdbb4b09882c75f2acd7ccf62020-11-25T02:24:42ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-04-01212849284910.3390/ijms21082849Possible Role of Amyloidogenic Evolvability in Dementia with Lewy Bodies: Insights from Transgenic Mice Expressing P123H β-SynucleinMasayo Fujita0Gilbert Ho1Yoshiki Takamatsu2Ryoko Wada3Kazutaka Ikeda4Makoto Hashimoto5Addictive Substance Project, Tokyo Metropolitan Institute of Medical Sciences, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, JapanPCND Neuroscience Research Institute, Poway, CA 92063, USALaboratory of Parkinson’s Disease, Tokyo Metropolitan Institute of Medical Sciences, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, JapanLaboratory of Parkinson’s Disease, Tokyo Metropolitan Institute of Medical Sciences, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, JapanAddictive Substance Project, Tokyo Metropolitan Institute of Medical Sciences, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, JapanLaboratory of Parkinson’s Disease, Tokyo Metropolitan Institute of Medical Sciences, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, JapanDementia 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.https://www.mdpi.com/1422-0067/21/8/2849Dementia with Lewy bodies (DLB)α-synuclein (αS)β-synuclein (βS)P123H βStransgenic (Tg) miceamyloidogenic evolvability |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Masayo Fujita Gilbert Ho Yoshiki Takamatsu Ryoko Wada Kazutaka Ikeda Makoto Hashimoto |
spellingShingle |
Masayo Fujita Gilbert Ho Yoshiki Takamatsu Ryoko Wada Kazutaka Ikeda Makoto Hashimoto Possible Role of Amyloidogenic Evolvability in Dementia with Lewy Bodies: Insights from Transgenic Mice Expressing P123H β-Synuclein International Journal of Molecular Sciences Dementia with Lewy bodies (DLB) α-synuclein (αS) β-synuclein (βS) P123H βS transgenic (Tg) mice amyloidogenic evolvability |
author_facet |
Masayo Fujita Gilbert Ho Yoshiki Takamatsu Ryoko Wada Kazutaka Ikeda Makoto Hashimoto |
author_sort |
Masayo Fujita |
title |
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_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_sort |
possible role of amyloidogenic evolvability in dementia with lewy bodies: insights from transgenic mice expressing p123h β-synuclein |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2020-04-01 |
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. |
topic |
Dementia with Lewy bodies (DLB) α-synuclein (αS) β-synuclein (βS) P123H βS transgenic (Tg) mice amyloidogenic evolvability |
url |
https://www.mdpi.com/1422-0067/21/8/2849 |
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