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

Masayo Fujita; Gilbert Ho; Yoshiki Takamatsu; Ryoko Wada; Kazutaka Ikeda; Makoto Hashimoto

doi:10.3390/ijms21082849

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

International Journal of Molecular Sciences ◽

10.3390/ijms21082849 ◽

2020 ◽

Vol 21 (8) ◽

pp. 2849

Author(s):

Masayo Fujita ◽

Gilbert Ho ◽

Yoshiki Takamatsu ◽

Ryoko Wada ◽

Kazutaka Ikeda ◽

...

Keyword(s):

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Gene Mutations ◽

Major Constituent ◽

Motor Deficits ◽

Missense Mutations ◽

Axonal Swelling ◽

Disease Modifying Therapy ◽

Progressive Neurodegeneration ◽

Disease Modifying

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.

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Toward a Disease-Modifying Therapy of Alpha-Synucleinopathies: New Molecules and New Approaches Came into the Limelight

Molecules ◽

10.3390/molecules26237351 ◽

2021 ◽

Vol 26 (23) ◽

pp. 7351

Author(s):

Matthew Upcott ◽

Kirill D. Chaprov ◽

Vladimir L. Buchman

Keyword(s):

Clinical Trials ◽

Lewy Bodies ◽

Alpha Synuclein ◽

Therapeutic Window ◽

Disease Modifying Therapy ◽

Stage Of Development ◽

Phase Ii Clinical Trials ◽

Modifying Effect ◽

Disease Modifying ◽

Alpha Synuclein Aggregation

The accumulation of the various products of alpha-synuclein aggregation has been associated with the etiology and pathogenesis of several neurodegenerative conditions, including both familial and sporadic forms of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). It is now well established that the aggregation and spread of alpha-synuclein aggregation pathology activate numerous pathogenic mechanisms that contribute to neurodegeneration and, ultimately, to disease progression. Therefore, the development of a safe and effective disease-modifying therapy that limits or prevents the accumulation of the toxic intermediate products of alpha-synuclein aggregation and the spread of alpha-synuclein aggregation pathology could provide significant positive clinical outcomes in PD/DLB cohorts. It has been suggested that this goal can be achieved by reducing the intracellular and/or extracellular levels of monomeric and already aggregated alpha-synuclein. The principal aim of this review is to critically evaluate the potential of therapeutic strategies that target the post-transcriptional steps of alpha-synuclein production and immunotherapy-based approaches to alpha-synuclein degradation in PD/DLB patients. Strategies aimed at the downregulation of alpha-synuclein production are at an early preclinical stage of drug development and, although they have shown promise in animal models of alpha-synuclein aggregation, many limitations need to be resolved before in-human clinical trials can be seriously considered. In contrast, many strategies aimed at the degradation of alpha-synuclein using immunotherapeutic approaches are at a more advanced stage of development, with some in-human Phase II clinical trials currently in progress. Translational barriers for both strategies include the limitations of alpha-synuclein aggregation models, poor understanding of the therapeutic window for the alpha-synuclein knockdown, and variability in alpha-synuclein pathology across patient cohorts. Overcoming such barriers should be the main focus of further studies. However, it is already clear that these strategies do have the potential to achieve a disease-modifying effect in PD and DLB.

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Nigral Iron Elevation Is an Invariable Feature of Parkinson’s Disease and Is a Sufficient Cause of Neurodegeneration

BioMed Research International ◽

10.1155/2014/581256 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 76

Author(s):

Scott Ayton ◽

Peng Lei

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Neurodegenerative Disorder ◽

Motor Deficits ◽

Disease Mechanism ◽

Disease Modifying Therapy ◽

Disease Modifying Therapies ◽

Sufficient Cause ◽

Disease Modifying

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by motor deficits accompanying degeneration of substantia nigra pars compactor (SNc) neurons. Although familial forms of the disease exist, the cause of sporadic PD is unknown. Symptomatic treatments are available for PD, but there are no disease modifying therapies. While the neurodegenerative processes in PD may be multifactorial, this paper will review the evidence that prooxidant iron elevation in the SNc is an invariable feature of sporadic and familial PD forms, participates in the disease mechanism, and presents as a tractable target for a disease modifying therapy.

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RAB39B gene mutations are not a common cause of Parkinson's disease or dementia with Lewy bodies

Neurobiology of Aging ◽

10.1016/j.neurobiolaging.2016.03.021 ◽

2016 ◽

Vol 45 ◽

pp. 107-108 ◽

Cited By ~ 17

Author(s):

Kyndall Hodges ◽

Sheridan S. Brewer ◽

Catherine Labbé ◽

Alexandra I. Soto-Ortolaza ◽

Ronald L. Walton ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Gene Mutations ◽

Common Cause

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High Frequency of GBA Gene Mutations in Dementia With Lewy Bodies Among Ashkenazi Jews

JAMA Neurology ◽

10.1001/jamaneurol.2016.1593 ◽

2016 ◽

Vol 73 (12) ◽

pp. 1448 ◽

Cited By ~ 27

Author(s):

Tamara Shiner ◽

Anat Mirelman ◽

Mali Gana Weisz ◽

Anat Bar-Shira ◽

Elissa Ash ◽

...

Keyword(s):

High Frequency ◽

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Gene Mutations ◽

Ashkenazi Jews ◽

Gba Gene

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Filamentous nerve cell inclusions in neurodegenerative diseases: tauopathies and alpha-synucleinopathies

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.1999.0466 ◽

1999 ◽

Vol 354 (1386) ◽

pp. 1101-1118 ◽

Cited By ~ 113

Author(s):

Michel Goedert

Keyword(s):

Neurodegenerative Diseases ◽

Dementia With Lewy Bodies ◽

Late Onset ◽

Lewy Bodies ◽

Corticobasal Degeneration ◽

New Work ◽

Missense Mutations ◽

Protein Tau ◽

Frontotemporal Dementias ◽

Filamentous Inclusions

Alzheimer'sdisease and Parkinson'sdisease are the most common neurodegenerative diseases. They are characterized by the degeneration of selected populations of nerve cells that develop filamentous inclusions before degeneration. The neuronal inclusions of Alzheimer'sdisease are made of the microtubule–associated protein tau, in a hyperphosphorylated state. Recent work has shown that the filamentous inclusions of Parkinson'sdisease are made of the protein α–synuclein and that rare, familial forms of Parkinson'sdisease are caused by missense mutations in the α–synuclein gene. Besides Parkinson'sdisease, the filamentous inclusions of two additional neurodegenerative diseases, namely dementia with Lewy bodies and multiple system atrophy, have also been found to be made of α–synuclein. Abundant filamentous tau inclusions are not limited to Alzheimer'sdisease. They are the defining neuropathological characteristic of frontotemporal dementias such as Pick'sdisease, and of progressive supranuclear palsy and corticobasal degeneration. The recent discovery of mutations in the tau gene in familial forms of frontotemporal dementia has provided a direct link between tau dysfunction and dementing disease. The new work has established that tauopathies and α–synucleinopathies account for most late–onset neurodegenerative diseases in man. The formation of intracellular filamentous inclusions might be the gain of toxic function that leads to the demise of affected brain cells.

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Contribution of rare homozygous and compound heterozygous VPS13C missense mutations to dementia with Lewy bodies and Parkinson’s disease

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01121-w ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Stefanie Smolders ◽

◽

Stéphanie Philtjens ◽

David Crosiers ◽

Anne Sieben ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Early Onset ◽

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Lewy Body Disease ◽

Compound Heterozygous ◽

Missense Mutations ◽

Increased Risk ◽

Vacuolar Protein

AbstractDementia with Lewy bodies (DLB) and Parkinson’s disease (PD) are clinically, pathologically and etiologically disorders embedded in the Lewy body disease (LBD) continuum, characterized by neuronal α-synuclein pathology. Rare homozygous and compound heterozygous premature termination codon (PTC) mutations in the Vacuolar Protein Sorting 13 homolog C gene (VPS13C) are associated with early-onset recessive PD. We observed in two siblings with early-onset age (< 45) and autopsy confirmed DLB, compound heterozygous missense mutations in VPS13C, p.Trp395Cys and p.Ala444Pro, inherited from their healthy parents in a recessive manner. In lymphoblast cells of the index patient, the missense mutations reduced VPS13C expression by 90% (p = 0.0002). Subsequent, we performed targeted resequencing of VPS13C in 844 LBD patients and 664 control persons. Using the optimized sequence kernel association test, we obtained a significant association (p = 0.0233) of rare VPS13C genetic variants (minor allele frequency ≤ 1%) with LBD. Among the LBD patients, we identified one patient with homozygous missense mutations and three with compound heterozygous missense mutations in trans position, indicative for recessive inheritance. In four patients with compound heterozygous mutations, we were unable to determine trans position. The frequency of LBD patient carriers of proven recessive compound heterozygous missense mutations is 0.59% (5/844). In autopsy brain tissue of two unrelated LBD patients, the recessive compound heterozygous missense mutations reduced VPS13C expression. Overexpressing of wild type or mutant VPS13C in HeLa or SH-SY5Y cells, demonstrated that the mutations p.Trp395Cys or p.Ala444Pro, abolish the endosomal/lysosomal localization of VPS13C. Overall, our data indicate that rare missense mutations in VPS13C are associated with LBD and recessive compound heterozygous missense mutations might have variable effects on the expression and functioning of VPS13C. We conclude that comparable to the recessive inherited PTC mutations in VPS13C, combinations of rare recessive compound heterozygous missense mutations reduce VPS13C expression and contribute to increased risk of LBD.

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Differential regulation of wild-type and mutant alpha-synuclein binding to synaptic membranes by cytosolic factors

BMC Neuroscience ◽

10.1186/1471-2202-9-92 ◽

2008 ◽

Vol 9 (1) ◽

Cited By ~ 17

Author(s):

Sabine Wislet-Gendebien ◽

Naomi P Visanji ◽

Shawn N Whitehead ◽

Diana Marsilio ◽

Weimin Hou ◽

...

Keyword(s):

Cellular Localization ◽

Membrane Binding ◽

Lewy Bodies ◽

Alpha Synuclein ◽

Major Constituent ◽

Synaptic Membranes ◽

Synaptic Membrane ◽

Missense Mutations ◽

Cytosolic Factors ◽

Brain Cytosol

Abstract Background Alpha-Synuclein (α-syn), a 140 amino acid protein associated with presynaptic membranes in brain, is a major constituent of Lewy bodies in Parkinson's disease (PD). Three missense mutations (A30P, A53T and E46K) in the α-syn gene are associated with rare autosomal dominant forms of familial PD. However, the regulation of α-syn's cellular localization in neurons and the effects of the PD-linked mutations are poorly understood. Results In the present study, we analysed the ability of cytosolic factors to regulate α-syn binding to synaptic membranes. We show that co-incubation with brain cytosol significantly increases the membrane binding of normal and PD-linked mutant α-syn. To characterize cytosolic factor(s) that modulate α-syn binding properties, we investigated the ability of proteins, lipids, ATP and calcium to modulate α-syn membrane interactions. We report that lipids and ATP are two of the principal cytosolic components that modulate Wt and A53T α-syn binding to the synaptic membrane. We further show that 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine (C16:0 PAF) is one of the principal lipids found in complex with cytosolic proteins and is required to enhance α-syn interaction with synaptic membrane. In addition, the impaired membrane binding observed for A30P α-syn was significantly mitigated by the presence of protease-sensitive factors in brain cytosol. Conclusion These findings suggest that endogenous brain cytosolic factors regulate Wt and mutant α-syn membrane binding, and could represent potential targets to influence α-syn solubility in brain.

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Potentials of autophagy enhancing natural products in the treatment of Parkinson disease

Drug Metabolism and Personalized Therapy ◽

10.1515/dmdi-2021-0128 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Taiwo G. Olubodun-Obadun ◽

Ismail O. Ishola ◽

Olufunmilayo O. Adeyemi

Keyword(s):

Natural Products ◽

Parkinson Disease ◽

Lewy Bodies ◽

Motor Symptoms ◽

Public Health Burden ◽

Disease Modifying Therapy ◽

Novel Approach ◽

Autophagy Pathway ◽

Disease Modifying ◽

Non Motor Symptoms

Abstract Parkinson disease (PD) is a progressive neurodegenerative movement disorder characterized by motor and non-motor symptoms due to loss of striatal dopaminergic neurons and disruption of degradation signaling leading to the formation of Lewy bodies (aggregation of α-synuclein). Presently, there are no disease modifying therapy for PD despite improvement in the understanding of the disease pathogenesis. However, the drugs currently used in PD management provide symptomatic relieve for motor symptoms without significant improvement in non-motor complications, thus, a public health burden on caregivers and healthcare systems. There is therefore the need to discover disease modifying therapy with strong potential to halt the disease progression. Recent trend has shown that the dysfunction of lysosomal-autophagy pathway is highly implicated in PD pathology, hence, making autophagy a key player owing to its involvement in degradation and clearance of misfolded α-synuclein (a major hallmark in PD pathology). In this review, we described the current drugs/strategy in the management of PD including targeting the autophagy pathway as a novel approach that could serve as potential intervention for PD management. The discovery of small molecules or natural products capable of enhancing autophagy mechanism could be a promising strategy for PD treatment.

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