scholarly journals The α-synuclein hereditary mutation E46K unlocks a more stable, pathogenic fibril structure

2019 ◽  
Author(s):  
David R. Boyer ◽  
Binsen Li ◽  
Chuanqi Sun ◽  
Weijia Fan ◽  
Kang Zhou ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Clinical Picture ◽  
Lewy Body ◽  
Strong Association ◽  
Lewy Body Dementia ◽  
Salt Bridge ◽  
Wild Type ◽  
Fibril Structure ◽  
Amyloid Aggregates

AbstractAggregation of α-synuclein is a defining molecular feature of Parkinson’s disease, Lewy Body Dementia, and Multiple Systems Atrophy. Hereditary mutations in α-synuclein are linked to both Parkinson’s disease and Lewy Body Dementia; in particular, patients bearing the E46K disease mutation manifest a clinical picture of parkinsonism and Lewy Body Dementia, and E46K creates more pathogenic fibrils in vitro. Understanding the effect of these hereditary mutations on α-synuclein fibril structure is fundamental to α-synuclein biology. We therefore determined the cryoEM structure of α-synuclein fibrils containing the hereditary E46K mutation. The 2.5 Å structure reveals a symmetric double protofilament in which the molecules adopt a vastly re-arranged, lower energy fold compared to wild-type fibrils. We propose that the E46K misfolding pathway avoids electrostatic repulsion between K46 and K80, a residue pair which forms the E46-K80 salt-bridge in the wild-type fibril structure. We hypothesize that under our conditions the wild-type fold does not reach this deeper energy well of the E46K fold because the E46-K80 salt bridge diverts α-synuclein into a kinetic trap – a shallower, more accessible energy minimum. The E46K mutation apparently unlocks a more stable and pathogenic fibril structure.Significance StatementParkinson’s is the second most prevalent neurodegenerative condition, leading to movement disorders, and dementia in some cases. Because of the strong association of this condition with amyloid aggregates of the protein α-synuclein, structural understanding of these amyloid aggregates may be the path to eventual therapies. Our study of the structure of a variant α-synuclein inherited in families afflicted with a clinical picture of parkinsonism and Lewy Body Dementia supplements recent structures of the wild type structure, and shows how a single residue change can result in a greatly changed structure that may underlie the inherited form of the disease.

scholarly journals The α-synuclein hereditary mutation E46K unlocks a more stable, pathogenic fibril structure

2020 ◽  
Vol 117 (7) ◽  
pp. 3592-3602 ◽  
Author(s):  
David R. Boyer ◽  
Binsen Li ◽  
Chuanqi Sun ◽  
Weijia Fan ◽  
Kang Zhou ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Body ◽  
Lewy Body Dementia ◽  
Salt Bridge ◽  
Wild Type ◽  
Molecular Feature ◽  
Multiple Systems ◽  
Fibril Structure

Aggregation of α-synuclein is a defining molecular feature of Parkinson’s disease, Lewy body dementia, and multiple systems atrophy. Hereditary mutations in α-synuclein are linked to both Parkinson’s disease and Lewy body dementia; in particular, patients bearing the E46K disease mutation manifest a clinical picture of parkinsonism and Lewy body dementia, and E46K creates more pathogenic fibrils in vitro. Understanding the effect of these hereditary mutations on α-synuclein fibril structure is fundamental to α-synuclein biology. We therefore determined the cryo-electron microscopy (cryo-EM) structure of α-synuclein fibrils containing the hereditary E46K mutation. The 2.5-Å structure reveals a symmetric double protofilament in which the molecules adopt a vastly rearranged, lower energy fold compared to wild-type fibrils. We propose that the E46K misfolding pathway avoids electrostatic repulsion between K46 and K80, a residue pair which form the E46-K80 salt bridge in the wild-type fibril structure. We hypothesize that, under our conditions, the wild-type fold does not reach this deeper energy well of the E46K fold because the E46-K80 salt bridge diverts α-synuclein into a kinetic trap—a shallower, more accessible energy minimum. The E46K mutation apparently unlocks a more stable and pathogenic fibril structure.

scholarly journals Cross-platform transcriptional profiling identifies common and distinct molecular pathologies in Lewy body diseases

2021 ◽  
Author(s):  
Rahel Feleke ◽  
Regina H. Reynolds ◽  
Amy M. Smith ◽  
Bension Tilley ◽  
Sarah A. Gagliano Taliun ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Diseases ◽  
Lewy Body ◽  
Molecular Mechanisms ◽  
Lewy Bodies ◽  
Subsequent Development ◽  
Lewy Body Dementia ◽  
Anterior Cingulate ◽  
Lewy Body Diseases

AbstractParkinson’s disease (PD), Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB) are three clinically, genetically and neuropathologically overlapping neurodegenerative diseases collectively known as the Lewy body diseases (LBDs). A variety of molecular mechanisms have been implicated in PD pathogenesis, but the mechanisms underlying PDD and DLB remain largely unknown, a knowledge gap that presents an impediment to the discovery of disease-modifying therapies. Transcriptomic profiling can contribute to addressing this gap, but remains limited in the LBDs. Here, we applied paired bulk-tissue and single-nucleus RNA-sequencing to anterior cingulate cortex samples derived from 28 individuals, including healthy controls, PD, PDD and DLB cases (n = 7 per group), to transcriptomically profile the LBDs. Using this approach, we (i) found transcriptional alterations in multiple cell types across the LBDs; (ii) discovered evidence for widespread dysregulation of RNA splicing, particularly in PDD and DLB; (iii) identified potential splicing factors, with links to other dementia-related neurodegenerative diseases, coordinating this dysregulation; and (iv) identified transcriptomic commonalities and distinctions between the LBDs that inform understanding of the relationships between these three clinical disorders. Together, these findings have important implications for the design of RNA-targeted therapies for these diseases and highlight a potential molecular “window” of therapeutic opportunity between the initial onset of PD and subsequent development of Lewy body dementia.

scholarly journals Dementia with Parkinson's disease: Clinical diagnosis, neuropsychological aspects and treatment

2008 ◽  
Vol 2 (4) ◽  
pp. 261-266
Author(s):  
Jorge Lorenzo Otero
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Body ◽  
Task Force ◽  
Lewy Body Dementia ◽  
Data Bases ◽  
Main Text ◽  
Clinical Diagnoses ◽  
Movement Disorder Society ◽  
Selection Of

Abstract Dementia with Parkinson's disease represents a controversial issue in the complex group of alpha-synucleinopathies. The author acknowledges the concept of a "continuum" between Parkinson disease's (PD), Lewy body dementia (LBD), and dementia in Parkinson's disease (PDD). However, the practicing neurologist needs to identify the phenotypic signs of each dementia. The treatment and prognosis are different in spite of the overlaps between them. The main aim of this review was to characterize the clinical diagnoses of dementia associated with Parkinson's disease (PDD). Secondarily, the review discussed some epidemiological and neuropsychological issues. Selection of articles was not systematic and reflects the author's opinion, where the main text selected was the recommendations from the Movement Disorder Society Task Force for PDD diagnosis. The Pub Med, OVID, and Proquest data bases were used for the search.

scholarly journals Genetic modifiers of risk and age at onset in GBA associated Parkinson’s disease and Lewy body dementia

Brain ◽  
2019 ◽  
Vol 143 (1) ◽  
pp. 234-248 ◽  
Author(s):  
Cornelis Blauwendraat ◽  
Xylena Reed ◽  
Lynne Krohn ◽  
Karl Heilbron ◽  
Sara Bandres-Ciga ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Risk ◽  
Lewy Body ◽  
Disease Risk ◽  
Genetic Risk Score ◽  
Age At Onset ◽  
Lewy Body Dementia ◽  
Risk Variants ◽  
Genome Wide

Abstract Parkinson’s disease is a genetically complex disorder. Multiple genes have been shown to contribute to the risk of Parkinson’s disease, and currently 90 independent risk variants have been identified by genome-wide association studies. Thus far, a number of genes (including SNCA, LRRK2, and GBA) have been shown to contain variability across a spectrum of frequency and effect, from rare, highly penetrant variants to common risk alleles with small effect sizes. Variants in GBA, encoding the enzyme glucocerebrosidase, are associated with Lewy body diseases such as Parkinson’s disease and Lewy body dementia. These variants, which reduce or abolish enzymatic activity, confer a spectrum of disease risk, from 1.4- to >10-fold. An outstanding question in the field is what other genetic factors that influence GBA-associated risk for disease, and whether these overlap with known Parkinson’s disease risk variants. Using multiple, large case-control datasets, totalling 217 165 individuals (22 757 Parkinson’s disease cases, 13 431 Parkinson’s disease proxy cases, 622 Lewy body dementia cases and 180 355 controls), we identified 1691 Parkinson’s disease cases, 81 Lewy body dementia cases, 711 proxy cases and 7624 controls with a GBA variant (p.E326K, p.T369M or p.N370S). We performed a genome-wide association study and analysed the most recent Parkinson’s disease-associated genetic risk score to detect genetic influences on GBA risk and age at onset. We attempted to replicate our findings in two independent datasets, including the personal genetics company 23andMe, Inc. and whole-genome sequencing data. Our analysis showed that the overall Parkinson’s disease genetic risk score modifies risk for disease and decreases age at onset in carriers of GBA variants. Notably, this effect was consistent across all tested GBA risk variants. Dissecting this signal demonstrated that variants in close proximity to SNCA and CTSB (encoding cathepsin B) are the most significant contributors. Risk variants in the CTSB locus were identified to decrease mRNA expression of CTSB. Additional analyses suggest a possible genetic interaction between GBA and CTSB and GBA p.N370S induced pluripotent cell-derived neurons were shown to have decreased cathepsin B expression compared to controls. These data provide a genetic basis for modification of GBA-associated Parkinson’s disease risk and age at onset, although the total contribution of common genetics variants is not large. We further demonstrate that common variability at genes implicated in lysosomal function exerts the largest effect on GBA associated risk for disease. Further, these results have implications for selection of GBA carriers for therapeutic interventions.

scholarly journals Nocturnal sleep enhances working memory training in Parkinson's disease but not Lewy body dementia

Brain ◽  
2012 ◽  
Vol 135 (9) ◽  
pp. 2789-2797 ◽  
Author(s):  
M. K. Scullin ◽  
L. M. Trotti ◽  
A. G. Wilson ◽  
S. A. Greer ◽  
D. L. Bliwise
Keyword(s):  
Parkinson’S Disease ◽  
Working Memory ◽  
Parkinson's Disease ◽  
Lewy Body ◽  
Lewy Body Dementia ◽  
Working Memory Training ◽  
Memory Training ◽  
Nocturnal Sleep

scholarly journals The emerging role of α-synuclein truncation in aggregation and disease

2020 ◽  
Vol 295 (30) ◽  
pp. 10224-10244 ◽  
Author(s):  
Zachary A. Sorrentino ◽  
Benoit I. Giasson
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Multiple System Atrophy ◽  
Lewy Body ◽  
Critical Role ◽  
Lewy Body Dementia ◽  
Proteolytic Processing ◽  
Neuronal Protein ◽  
Preventative Strategy

α-Synuclein (αsyn) is an abundant brain neuronal protein that can misfold and polymerize to form toxic fibrils coalescing into pathologic inclusions in neurodegenerative diseases, including Parkinson's disease, Lewy body dementia, and multiple system atrophy. These fibrils may induce further αsyn misfolding and propagation of pathologic fibrils in a prion-like process. It is unclear why αsyn initially misfolds, but a growing body of literature suggests a critical role of partial proteolytic processing resulting in various truncations of the highly charged and flexible carboxyl-terminal region. This review aims to 1) summarize recent evidence that disease-specific proteolytic truncations of αsyn occur in Parkinson's disease, Lewy body dementia, and multiple system atrophy and animal disease models; 2) provide mechanistic insights on how truncation of the amino and carboxyl regions of αsyn may modulate the propensity of αsyn to pathologically misfold; 3) compare experiments evaluating the prion-like properties of truncated forms of αsyn in various models with implications for disease progression; 4) assess uniquely toxic properties imparted to αsyn upon truncation; and 5) discuss pathways through which truncated αsyn forms and therapies targeted to interrupt them. Cumulatively, it is evident that truncation of αsyn, particularly carboxyl truncation that can be augmented by dysfunctional proteostasis, dramatically potentiates the propensity of αsyn to pathologically misfold into uniquely toxic fibrils with modulated prion-like seeding activity. Therapeutic strategies and experimental paradigms should operate under the assumption that truncation of αsyn is likely occurring in both initial and progressive disease stages, and preventing truncation may be an effective preventative strategy against pathologic inclusion formation.

Microglial activation in Parkinson's disease and Lewy body dementia: A PET study

NeuroImage ◽  
2008 ◽  
Vol 41 ◽  
pp. T116
Author(s):  
Daniela Rota ◽  
R.M. Moresco ◽  
S. Iannacone ◽  
I. Florea ◽  
V. Garibotto ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Body ◽  
Microglial Activation ◽  
Lewy Body Dementia
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