Abstract
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.
Highlights
Dementia with Lewy bodies (DLB) is the second most prevalent neurodegenerative dementia after Alzheimer’s disease (AD) [1]
If altered βS is involved in the pathogenesis of sporadic DLB, P123H βS Tg mice might represent a generalized model for investigating DLB mechanisms and therapy
genome wide association studies (GWAS) revealed that apolipoprotein E (APOE), a major risk factor for AD, might be a susceptibility gene linked to sporadic DLB (Figure 5) [43]
Summary
Dementia with Lewy bodies (DLB) is the second most prevalent neurodegenerative dementia after Alzheimer’s disease (AD) [1]. Autopsy tissue from a P123H βS patient exhibited typical αS pathology without evidence of βS aggregation, suggesting that P123H βS might be involved in the stimulation of αS aggregation by unknown mechanisms [8]. Neurodegenerative features such as lysosomal inclusions were identified in neurons expressing mutant βS [9,10]. We proposed that neurodegeneration in aging may be attributed to amyloidogeioc evolvability [11,12,13] In this context, the main objective of this paper is to discuss the possible involvement of amyloidogenic evolvability in the pathogenesis of DLB using transgenic (Tg) mice expressing P123H βS which developed progressive neurodegeneration [14]. If altered βS is involved in the pathogenesis of sporadic DLB, P123H βS Tg mice might represent a generalized model for investigating DLB mechanisms and therapy
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