Copper(II)-induced self-oligomerization of α-synuclein

α-Synuclein is a component of the abnormal protein depositions in senile plaques and Lewy bodies of Alzheimer's disease (AD) and Parkinson's disease respectively. The protein was suggested to provide a possible nucleation centre for plaque formation in AD via selective interaction with amyloid β/A4 protein (Aβ). We have shown previously that α-synuclein has experienced self-oligomerization when Aβ25-35 was present in an orientation-specific manner in the sequence. Here we examine this biochemically specific self-oligomerization with the use of various metals. Strikingly, copper(II) was the most effective metal ion affecting α-synuclein to form self-oligomers in the presence of coupling reagents such as dicyclohexylcarbodi-imide or N-(ethoxycarbonyl)-2-ethoxy-1,2-dihydroquinoline. The size distribution of the oligomers indicated that monomeric α-synuclein was oligomerized sequentially. The copper-induced oligomerization was shown to be suppressed as the acidic C-terminus of α-synuclein was truncated by treatment with endoproteinase Asp-N. In contrast, the Aβ25-35-induced oligomerizations of the intact and truncated forms of α-synuclein were not affected. This clearly indicated that the copper-induced oligomerization was dependent on the acidic C-terminal region and that its underlying biochemical mechanism was distinct from that of the Aβ25-35-induced oligomerization. Although the physiological or pathological relevance of the oligomerization remains currently elusive, the common outcome of α-synuclein on treatment with copper or Aβ25-35 might be useful in understanding neurodegenerative disorders in molecular terms. In addition, abnormal copper homoeostasis could be considered as one of the risk factors for the development of disorders such as AD or Parkinson's disease.

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Subcellular orchestration of alpha-synuclein variants in Parkinson’s disease brains revealed by 3D multicolor STED microscopy

10.1101/470476 ◽

2018 ◽

Cited By ~ 7

Author(s):

Tim E. Moors ◽

Christina A. Maat ◽

Daniel Niedieker ◽

Daniel Mona ◽

Dennis Petersen ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Lewy Bodies ◽

Distribution Patterns ◽

Alpha Synuclein ◽

Label Free ◽

Post Translational Modifications ◽

Sted Microscopy ◽

C Terminus

AbstractPost-translational modifications of alpha-synuclein (aSyn), particularly phosphorylation at Serine 129 (Ser129-p) and truncation of its C-terminus (CTT), have been implicated in Parkinson’s disease (PD) pathology. To gain more insight in the relevance of Ser129-p and CTT aSyn under physiological and pathological conditions, we investigated their subcellular distribution patterns in normal aged and PD brains using highly-selective antibodies in combination with 3D multicolor STED microscopy. We show that CTT aSyn localizes in mitochondria in PD patients and controls, whereas the organization of Ser129-p in a cytoplasmic network is strongly associated with pathology. Nigral Lewy bodies show an onion skin-like architecture, with a structured framework of Ser129-p aSyn and neurofilaments encapsulating CTT aSyn in their core, which displayed high content of proteins and lipids by label-free CARS microscopy. The subcellular phenotypes of antibody-labeled pathology identified in this study provide evidence for a crucial role of Ser129-p aSyn in Lewy body formation.

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Cytotoxicity and Mitochondrial Dysregulation Caused by α-Synuclein in Dictyostelium discoideum

Cells ◽

10.3390/cells9102289 ◽

2020 ◽

Vol 9 (10) ◽

pp. 2289 ◽

Cited By ~ 1

Author(s):

Sanjanie Fernando ◽

Claire Y. Allan ◽

Katelyn Mroczek ◽

Xavier Pearce ◽

Oana Sanislav ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dictyostelium Discoideum ◽

Mitochondrial Function ◽

Molecular Mechanisms ◽

Lewy Bodies ◽

Alpha Synuclein ◽

Cell Cortex ◽

Mutant Proteins ◽

C Terminus

Alpha synuclein has been linked to both sporadic and familial forms of Parkinson’s disease (PD) and is the most abundant protein in Lewy bodies a hallmark of Parkinson’s disease. The function of this protein and the molecular mechanisms underlying its toxicity are still unclear, but many studies have suggested that the mechanism of α-synuclein toxicity involves alterations to mitochondrial function. Here we expressed human α-synuclein and two PD-causing α-synuclein mutant proteins (with a point mutation, A53T, and a C-terminal 20 amino acid truncation) in the eukaryotic model Dictyostelium discoideum. Mitochondrial disease has been well studied in D. discoideum and, unlike in mammals, mitochondrial dysfunction results in a clear set of defective phenotypes. These defective phenotypes are caused by the chronic hyperactivation of the cellular energy sensor, AMP-activated protein kinase (AMPK). Expression of α-synuclein wild type and mutant forms was toxic to the cells and mitochondrial function was dysregulated. Some but not all of the defective phenotypes could be rescued by down regulation of AMPK revealing both AMPK-dependent and -independent mechanisms. Importantly, we also show that the C-terminus of α-synuclein is required and sufficient for the localisation of the protein to the cell cortex in D. discoideum.

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It Is Time to Study Overlapping Molecular and Circuit Pathophysiologies in Alzheimer’s and Lewy Body Disease Spectra

Frontiers in Systems Neuroscience ◽

10.3389/fnsys.2021.777706 ◽

2021 ◽

Vol 15 ◽

Author(s):

Noritaka Wakasugi ◽

Takashi Hanakawa

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Continuous Spectrum ◽

Lewy Body ◽

Lewy Bodies ◽

Amyloid Β ◽

Lewy Body Disease ◽

Common Mechanism ◽

Protein Accumulation ◽

The Brain

Alzheimer’s disease (AD) is the leading cause of dementia due to neurodegeneration and is characterized by extracellular senile plaques composed of amyloid β1–42 (Aβ) as well as intracellular neurofibrillary tangles consisting of phosphorylated tau (p-tau). Dementia with Lewy bodies constitutes a continuous spectrum with Parkinson’s disease, collectively termed Lewy body disease (LBD). LBD is characterized by intracellular Lewy bodies containing α-synuclein (α-syn). The core clinical features of AD and LBD spectra are distinct, but the two spectra share common cognitive and behavioral symptoms. The accumulation of pathological proteins, which acquire pathogenicity through conformational changes, has long been investigated on a protein-by-protein basis. However, recent evidence suggests that interactions among these molecules may be critical to pathogenesis. For example, Aβ/tau promotes α-syn pathology, and α-syn modulates p-tau pathology. Furthermore, clinical evidence suggests that these interactions may explain the overlapping pathology between AD and LBD in molecular imaging and post-mortem studies. Additionally, a recent hypothesis points to a common mechanism of prion-like progression of these pathological proteins, via neural circuits, in both AD and LBD. This suggests a need for understanding connectomics and their alterations in AD and LBD from both pathological and functional perspectives. In AD, reduced connectivity in the default mode network is considered a hallmark of the disease. In LBD, previous studies have emphasized abnormalities in the basal ganglia and sensorimotor networks; however, these account for movement disorders only. Knowledge about network abnormalities common to AD and LBD is scarce because few previous neuroimaging studies investigated AD and LBD as a comprehensive cohort. In this paper, we review research on the distribution and interactions of pathological proteins in the brain in AD and LBD, after briefly summarizing their clinical and neuropsychological manifestations. We also describe the brain functional and connectivity changes following abnormal protein accumulation in AD and LBD. Finally, we argue for the necessity of neuroimaging studies that examine AD and LBD cases as a continuous spectrum especially from the proteinopathy and neurocircuitopathy viewpoints. The findings from such a unified AD and Parkinson’s disease (PD) cohort study should provide a new comprehensive perspective and key data for guiding disease modification therapies targeting the pathological proteins in AD and LBD.

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Neuropathology of dementia in patients with Parkinson’s disease: a systematic review of autopsy studies

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2019-321111 ◽

2019 ◽

pp. jnnp-2019-321111 ◽

Cited By ~ 10

Author(s):

Callum Smith ◽

Naveed Malek ◽

Katherine Grosset ◽

Breda Cullen ◽

Steve Gentleman ◽

...

Keyword(s):

Systematic Review ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cognitive Decline ◽

Lewy Bodies ◽

Amyloid Β ◽

Amyloid Angiopathy ◽

Comparison Groups ◽

Registration Number ◽

Rapid Cognitive Decline

BackgroundDementia is a common, debilitating feature of late Parkinson’s disease (PD). PD dementia (PDD) is associated with α-synuclein propagation, but coexistent Alzheimer’s disease (AD) pathology may coexist. Other pathologies (cerebrovascular, transactive response DNA-binding protein 43 (TDP-43)) may also influence cognition. We aimed to describe the neuropathology underlying dementia in PD.MethodsSystematic review of autopsy studies published in English involving PD cases with dementia. Comparison groups included PD without dementia, AD, dementia with Lewy bodies (DLB) and healthy controls.Results44 reports involving 2002 cases, 57.2% with dementia, met inclusion criteria. While limbic and neocortical α-synuclein pathology had the strongest association with dementia, between a fifth and a third of all PD cases in the largest studies had comorbid AD. In PD cases with dementia, tau pathology was moderate or severe in around a third, and amyloid-β pathology was moderate or severe in over half. Amyloid-β was associated with a more rapid cognitive decline and earlier mortality, and in the striatum, distinguished PDD from DLB. Positive correlations between multiple measures of α-synuclein, tau and amyloid-β were found. Cerebrovascular and TDP-43 pathologies did not generally contribute to dementia in PD. TDP-43 and amyloid angiopathy correlated with coexistent Alzheimer pathology.ConclusionsWhile significant α-synuclein pathology is the main substrate of dementia in PD, coexistent pathologies are common. In particular, tau and amyloid-β pathologies independently contribute to the development and pattern of cognitive decline in PD. Their presence should be assessed in future clinical trials where dementia is a key outcome measure.Trial registration number CRD42018088691.

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CSF amyloid-β-peptides in Alzheimer's disease, dementia with Lewy bodies and Parkinson's disease dementia

Brain ◽

10.1093/brain/awl063 ◽

2006 ◽

Vol 129 (5) ◽

pp. 1177-1187 ◽

Cited By ~ 129

Author(s):

Mirko Bibl ◽

Brit Mollenhauer ◽

Hermann Esselmann ◽

Piotr Lewczuk ◽

Hans-Wolfgang Klafki ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Parkinson’S Disease ◽

Alzheimer's Disease ◽

Parkinson's Disease ◽

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Amyloid Β ◽

Parkinson’S Disease Dementia ◽

Alzheimer’S Disease Dementia

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α-Synuclein TransgenicDrosophilaAs a Model of Parkinson's Disease and Related Synucleinopathies

Parkinson s Disease ◽

10.4061/2011/212706 ◽

2011 ◽

Vol 2011 ◽

pp. 1-7 ◽

Cited By ~ 3

Author(s):

Hideya Mizuno ◽

Nobuhiro Fujikake ◽

Keiji Wada ◽

Yoshitaka Nagai

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Drosophila Melanogaster ◽

Large Scale ◽

Critical Role ◽

Lewy Bodies ◽

Transgenic Animals ◽

Increased Risk ◽

The Common ◽

Common Pathogenesis

α-Synuclein (α-Syn) is a major component of protein inclusions known as Lewy bodies, which are hallmarks of synucleinopathies such as Parkinson's disease (PD). Theα-Syn gene is one of the familial PD-causing genes and is also associated with an increased risk of sporadic PD. Numerous studies usingα-Syn expressing transgenic animals have indicated thatα-Syn plays a critical role in the common pathogenesis of synucleinopathies.Drosophila melanogasterhas several advantages for modeling human neurodegenerative diseases and is widely used for studying their pathomechanisms and therapies. In fact,Drosophilamodels expressingα-Syn have already been established and proven to replicate several features of human PD. In this paper, we review the current research on synucleinopathies usingα-SynDrosophilamodels and, moreover, explore the possibilities of these models for comprehensive genetic analyses and large-scale drug screening towards elucidating the molecular pathogenesis and developing therapies for synucleinopathies.

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Alzheimer’s disease tau is a prominent pathology in LRRK2 Parkinson’s disease

Acta Neuropathologica Communications ◽

10.1186/s40478-019-0836-x ◽

2019 ◽

Vol 7 (1) ◽

Cited By ~ 21

Author(s):

Michael X. Henderson ◽

Medha Sengupta ◽

John Q. Trojanowski ◽

Virginia M. Y. Lee

Keyword(s):

Alzheimer’S Disease ◽

Parkinson’S Disease ◽

Alzheimer's Disease ◽

Parkinson's Disease ◽

Clinical Presentation ◽

Lewy Bodies ◽

Amyloid Β ◽

Tau Pathology ◽

Mutation Carriers ◽

Familial Parkinson’S Disease

AbstractMutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson’s disease (PD). While the clinical presentation of LRRK2 mutation carriers is similar to that of idiopathic PD (iPD) patients, the neuropathology of LRRK2 PD is less clearly defined. Lewy bodies (LBs) composed of α-synuclein are a major feature of iPD, but are not present in all LRRK2 PD cases. There is some evidence that tau may act as a neuropathological substrate in LB-negative LRRK2 PD, but this has not been examined systematically. In the current study, we examined α-synuclein, tau, and amyloid β (Aβ) pathologies in 12 LRRK2 mutation carriers. We find that α-synuclein pathology is present in 63.6% of LRRK2 mutation carriers, but tau pathology can be found in 100% of carriers and is abundant in 91% of carriers. We further use an antibody which selectively binds Alzheimer’s disease (AD)-type tau and use quantitative analysis of tau pathology to demonstrate that AD tau is the prominent type of tau present in LRRK2 mutation carriers. Abundant Aβ pathology can also be found in LRRK2 mutation carriers and is consistent with comorbid AD pathology. Finally, we assessed the association of neuropathology with clinical features in LRRK2 mutation carriers and idiopathic individuals and find that LRRK2 PD shares clinical and pathological features of idiopathic PD. The prevalence of AD-type tau pathology in LRRK2 PD is an important consideration for understanding PD pathogenesis and refining clinical trial inclusion and progression criterion.

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