scholarly journals Luminescent conjugated oligothiophenes distinguish between α-synuclein assemblies of Parkinson’s disease and multiple system atrophy

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Therése Klingstedt ◽  
Bernardino Ghetti ◽  
Janice L. Holton ◽  
Helen Ling ◽  
K. Peter R. Nilsson ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Multiple System Atrophy ◽  
Lewy Bodies ◽  
Fluorescence Lifetime Imaging ◽  
Cytoplasmic Inclusions ◽  
Glial Cytoplasmic Inclusions ◽  
Lewy Pathology ◽  
Lifetime Imaging ◽  
The Difference

AbstractSynucleinopathies [Parkinson’s disease with or without dementia, dementia with Lewy bodies and multiple system atrophy] are neurodegenerative diseases that are defined by the presence of filamentous α-synuclein inclusions. We investigated the ability of luminescent conjugated oligothiophenes to stain the inclusions of Parkinson’s disease and multiple system atrophy. They stained the Lewy pathology of Parkinson’s disease and the glial cytoplasmic inclusions of multiple system atrophy. Spectral analysis of HS-68-stained inclusions showed a red shift in multiple system atrophy, but the difference with Parkinson’s disease was not significant. However, when inclusions were double-labelled for HS-68 and an antibody specific for α-synuclein phosphorylated at S129, they could be distinguished based on colour shifts with blue designated for Parkinson’s disease and red for multiple system atrophy. The inclusions of Parkinson’s disease and multiple system atrophy could also be distinguished using fluorescence lifetime imaging. These findings are consistent with the presence of distinct conformers of assembled α-synuclein in Parkinson’s disease and multiple system atrophy.

scholarly journals Structures of α-synuclein filaments from multiple system atrophy

2020 ◽  
Author(s):  
Manuel Schweighauser ◽  
Yang Shi ◽  
Airi Tarutani ◽  
Fuyuki Kametani ◽  
Alexey G. Murzin ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Human Brain ◽  
Multiple System Atrophy ◽  
Recombinant Proteins ◽  
Dementia With Lewy Bodies ◽  
Lewy Bodies ◽  
Two Dimensional ◽  
Filamentous Inclusions

Synucleinopathies are human neurodegenerative diseases that include multiple system atrophy (MSA), Parkinson’s disease, Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB) (1). Existing treatments are at best symptomatic. These diseases are characterised by the presence in brain cells of filamentous inclusions of α-synuclein, the formation of which is believed to cause disease (2, 3). However, the structures of α-synuclein filaments from human brain are not known. Here we show, using electron cryo-microscopy, that α-synuclein inclusions from MSA are made of two types of filaments, each of which consists of two different protofilaments. Non-proteinaceous molecules are present at the protofilament interfaces. By two-dimensional class averaging, we show that α-synuclein filaments from the brains of patients with MSA and DLB are different, suggesting that distinct conformers (or strains) characterise synucleinopathies. As was the case of tau assemblies (4–9), the structures of α-synuclein filaments extracted from the brains of individuals with MSA differ from those formed in vitro using recombinant proteins, with implications for understanding the mechanisms of aggregate propagation and neurodegeneration in human brain. These findings have diagnostic and potential therapeutic relevance, especially in view of the unmet clinical need to be able to image filamentous α-synuclein inclusions in human brain.

scholarly journals Autophagy in α-Synucleinopathies—An Overstrained System

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3143
Author(s):  
Lisa Fellner ◽  
Elisa Gabassi ◽  
Johannes Haybaeck ◽  
Frank Edenhofer
Keyword(s):  
Multiple System Atrophy ◽  
Dementia With Lewy Bodies ◽  
Trigger Point ◽  
Lewy Bodies ◽  
Cytoplasmic Inclusions ◽  
Glial Cytoplasmic Inclusions ◽  
Inclusion Formation ◽  
Intracytoplasmic Inclusion ◽  
Current Review ◽  
Disease Initiation

Alpha-synucleinopathies comprise progressive neurodegenerative diseases, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). They all exhibit the same pathological hallmark, which is the formation of α-synuclein positive deposits in neuronal or glial cells. The aggregation of α-synuclein in the cell body of neurons, giving rise to the so-called Lewy bodies (LBs), is the major characteristic for PD and DLB, whereas the accumulation of α-synuclein in oligodendroglial cells, so-called glial cytoplasmic inclusions (GCIs), is the hallmark for MSA. The mechanisms involved in the intracytoplasmic inclusion formation in neuronal and oligodendroglial cells are not fully understood to date. A possible mechanism could be an impaired autophagic machinery that cannot cope with the high intracellular amount of α-synuclein. In fact, different studies showed that reduced autophagy is involved in α-synuclein aggregation. Furthermore, altered levels of different autophagy markers were reported in PD, DLB, and MSA brains. To date, the trigger point in disease initiation is not entirely clear; that is, whether autophagy dysfunction alone suffices to increase α-synuclein or whether α-synuclein is the pathogenic driver. In the current review, we discuss the involvement of defective autophagy machinery in the formation of α-synuclein aggregates, propagation of α-synuclein, and the resulting neurodegenerative processes in α-synucleinopathies.

scholarly journals Clinical Manifestations of Parkinson's Disease and Parkinsonism

2003 ◽  
Vol 30 (S1) ◽  
pp. S2-S9 ◽  
Author(s):  
Doug Everett Hobson
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Differential Diagnosis ◽  
Multiple System Atrophy ◽  
Dementia With Lewy Bodies ◽  
Clinical Manifestations ◽  
Lewy Bodies ◽  
Accurate Diagnosis ◽  
Additional Information ◽  
Diagnosis And Prognosis

The most common disorder in a patient presenting to a movement disorder clinic will be parkinsonism. The challenge is to provide the patient with the most accurate diagnosis and prognosis possible. The assumption at the time of initial presentation of the clinical diagnosis of Parkinson's disease is often wrong (20-25%). Waiting to see the pattern of progression, and response to medication provides invaluable additional information. This manuscript summarizes the clinical manifestations of Parkinson's disease and the main akinetic-rigid syndromes (progressive supranuclear palsy, multiple system atrophy, cortical-basal ganglionic degeneration, and dementia with Lewy bodies) that make up the differential diagnosis.

scholarly journals Serum neuronal exosomes predict and differentiate Parkinson’s disease from atypical parkinsonism

2020 ◽  
Vol 91 (7) ◽  
pp. 720-729 ◽  
Author(s):  
Cheng Jiang ◽  
Franziska Hopfner ◽  
Antigoni Katsikoudi ◽  
Robert Hein ◽  
Candan Catli ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Multiple System Atrophy ◽  
Disease Progression ◽  
Lewy Bodies ◽  
Training Group ◽  
Cross Sectional Study ◽  
Atypical Parkinsonism ◽  
Serum Samples ◽  
Cross Sectional

ObjectiveParkinson’s disease is characterised neuropathologically by α-synuclein aggregation. Currently, there is no blood test to predict the underlying pathology or distinguish Parkinson’s from atypical parkinsonian syndromes. We assessed the clinical utility of serum neuronal exosomes as biomarkers across the spectrum of Parkinson’s disease, multiple system atrophy and other proteinopathies.MethodsWe performed a cross-sectional study of 664 serum samples from the Oxford, Kiel and Brescia cohorts consisting of individuals with rapid eye movement sleep behavioural disorder, Parkinson’s disease, dementia with Lewy bodies, multiple system atrophy, frontotemporal dementia, progressive supranuclear palsy, corticobasal syndrome and controls. Longitudinal samples were analysed from Parkinson’s and control individuals. We developed poly(carboxybetaine-methacrylate) coated beads to isolate L1 cell adhesion molecule (L1CAM)-positive extracellular vesicles with characteristics of exosomes and used mass spectrometry or multiplexed electrochemiluminescence to measure exosomal proteins.ResultsMean neuron-derived exosomal α-synuclein was increased by twofold in prodromal and clinical Parkinson’s disease when compared with multiple system atrophy, controls or other neurodegenerative diseases. With 314 subjects in the training group and 105 in the validation group, exosomal α-synuclein exhibited a consistent performance (AUC=0.86) in separating clinical Parkinson’s disease from controls across populations. Exosomal clusterin was elevated in subjects with non-α-synuclein proteinopathies. Combined neuron-derived exosomal α-synuclein and clusterin measurement predicted Parkinson’s disease from other proteinopathies with AUC=0.98 and from multiple system atrophy with AUC=0.94. Longitudinal sample analysis showed that exosomal α-synuclein remains stably elevated with Parkinson’s disease progression.ConclusionsIncreased α-synuclein egress in serum neuronal exosomes precedes the diagnosis of Parkinson’s disease, persists with disease progression and in combination with clusterin predicts and differentiates Parkinson’s disease from atypical parkinsonism.

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