α-Synuclein in blood exosomes immunoprecipitated using neuronal and oligodendroglial markers distinguishes Parkinson’s disease from multiple system atrophy

Dutta, Suman; Hornung, Simon; Kruayatidee, Adira; Maina, Katherine N.; Rosario, Irish Del; Paul, Kimberly C.; Wong, Darice Y.; Folle, Aline Duarte; Markovic, Daniela; Palma, Jose Alberto; Serrano, Geidy E.; Adler, Charles H.; Perlman, Susan; Poon, Wayne W.; Kang, Un Jung; Alcalay, Roy N.; Sklerov, Miriam; Gylys, Karen H.; Kaufmann, Horacio; Fogel, Brent L.; Bronstein, Jeff M.; Ritz, Beate; Bitan, Gal

doi:10.1007/s00401-021-02324-0

Cited by 106 publications

(176 citation statements)

References 71 publications

(97 reference statements)

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“…Furthermore, we reported a lower EV concentration and an increased EV size in human plasma samples from patients with Alzheimer's disease (AD) and related dementias [35]. In line with our results, a reduced exosome concentration in serum/plasma was observed in multiple system atrophy and Parkinson's disease patients, compared with controls [36]. Increased levels of total Tau, phosphorylated Thr181 Tau, and Aβ42 in neurally derived blood EVs were demonstrated to be an early marker for AD and cognitive decline progression, thus supporting the use of circulating EVs as a sort of "liquid biopsy" [37][38][39].…”

Section: Introductionsupporting

confidence: 88%

Plasma Small Extracellular Vesicles with Complement Alterations in GRN/C9orf72 and Sporadic Frontotemporal Lobar Degeneration

Bellini

Saraceno

Benussi

et al. 2022

Cells

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Cutting-edge research suggests endosomal/immune dysregulation in GRN/C9orf72-associated frontotemporal lobar degeneration (FTLD). In this retrospective study, we investigated plasma small extracellular vesicles (sEVs) and complement proteins in 172 subjects (40 Sporadic FTLD, 40 Intermediate/Pathological C9orf72 expansion carriers, and 49 Heterozygous/Homozygous GRN mutation carriers, 43 controls). Plasma sEVs (concentration, size) were analyzed by nanoparticle tracking analysis; plasma and sEVs C1q, C4, C3 proteins were quantified by multiplex assay. We demonstrated that genetic/sporadic FTLD share lower sEV concentrations and higher sEV sizes. The diagnostic performance of the two most predictive variables (sEV concentration/size ratio) was high (AUC = 0.91, sensitivity 85.3%, specificity 81.4%). C1q, C4, and C3 cargo per sEV is increased in genetic and sporadic FTLD. C4 (cargo per sEV, total sEV concentration) is increased in Sporadic FTLD and reduced in GRN+ Homozygous, suggesting its specific unbalance compared with Heterozygous cases. C3 plasma level was increased in genetic vs. sporadic FTLD. Looking at complement protein compartmentalization, in control subjects, the C3 and C4 sEV concentrations were roughly half that in respect to those measured in plasma; interestingly, this compartmentalization was altered in different ways in patients. These results suggest sEVs and complement proteins as potential therapeutic targets to mitigate neurodegeneration in FTLD.

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Section: Introductionsupporting

confidence: 88%

Plasma Small Extracellular Vesicles with Complement Alterations in GRN/C9orf72 and Sporadic Frontotemporal Lobar Degeneration

Bellini

Saraceno

Benussi

et al. 2022

Cells

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“…In this regard, α-syn oligomers have been detected in the plasma of PD patients, but it remains to be determined if their presence precedes neuronal loss ( 104 ). A recent study by Dutta and colleagues confirmed the presence of α-syn in the blood of patients by exosome immunoprecipitation using neuronal and oligodendroglial markers, observing significantly higher α-syn concentrations in MSA exosomes compared to PD and healthy controls ( 105 ). The use of skin biopsies containing autonomic nerve terminals has also been suggested as a potential alternative source to investigate the seeding capability of α-syn, with comparable sensitivity and specificity to CSF ( 106 ).…”

Section: Introductionmentioning

confidence: 89%

The Concept of α-Synuclein Strains and How Different Conformations May Explain Distinct Neurodegenerative Disorders

2021

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In the past few years, an increasing amount of studies primarily based on experimental models have investigated the existence of distinct α-synuclein strains and their different pathological effects. This novel concept could shed light on the heterogeneous nature of α-synucleinopathies, a group of disorders that includes Parkinson's disease, dementia with Lewy bodies and multiple system atrophy, which share as their key-molecular hallmark the abnormal aggregation of α-synuclein, a process that seems pivotal in disease pathogenesis according to experimental observations. However, the etiology of α-synucleinopathies and the initial events leading to the formation of α-synuclein aggregates remains elusive. Hence, the hypothesis that structurally distinct fibrillary assemblies of α-synuclein could have a causative role in the different disease phenotypes and explain, at least to some extent, their specific neurodegenerative, disease progression, and clinical presentation patterns is very appealing. Moreover, the presence of different α-synuclein strains might represent a potential biomarker for the diagnosis of these neurodegenerative disorders. In this regard, the recent use of super resolution techniques and protein aggregation assays has offered the possibility, on the one hand, to elucidate the conformation of α-synuclein pathogenic strains and, on the other hand, to cyclically amplify to detectable levels low amounts of α-synuclein strains in blood, cerebrospinal fluid and peripheral tissue from patients. Thus, the inclusion of these techniques could facilitate the differentiation between α-synucleinopathies, even at early stages, which is crucial for successful therapeutic intervention. This mini-review summarizes the current knowledge on α-synuclein strains and discusses its possible applications and potential benefits.

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“…More recently, in 2021, Dutta and colleagues analyzed the levels of α-Syn in neuronal (L1CAMimmunoprecipitated) and oligodendroglial (myelin oligodendrocyte glycoprotein-immunoprecipitated) EVs from serum or plasma of PD and MSA patients vs. HC [126]. They found that in both EV types, α-Syn levels significantly increased in the order HC<PD<MSA, in contrast with [125].…”

Section: α-Syn As Ev-transported Pd Biomarkermentioning

confidence: 99%

“…They found that in both EV types, α-Syn levels significantly increased in the order HC<PD<MSA, in contrast with [125]. Moreover, the ratio between α-Syn in oligodendroglial and neuronal EVs improved the distinction between the two synucleinopathies, with high sensitivity and specificity [126].…”

Section: α-Syn As Ev-transported Pd Biomarkermentioning

confidence: 99%

Extracellular Vesicles as Novel Diagnostic and Prognostic Biomarkers for Parkinson’s Disease

et al. 2021

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The elderly population will significantly increase in the next decade and, with it, the proportion of people affected by age-related diseases. Among them, one of the most invalidating is Parkinson's disease (PD), characterized by motor-and non-motor dysfunctions which strongly impair the quality of life of affected individuals. PD is characterized by the progressive degeneration of dopaminergic neurons, with consequent dopamine depletion, and the accumulation of misfolded α-synuclein aggregates. Although 150 years have passed since PD first description, no effective therapies are currently available, but only palliative treatments. Importantly, PD is often diagnosed when the neuronal loss is elevated, making difficult any therapeutic intervention. In this context, two key challenges remain unanswered: (i) the early diagnosis to avoid the insurgence of irreversible symptoms; and (ii) the reliable monitoring of therapy efficacy. Research strives to identify novel biomarkers for PD diagnosis, prognosis, and therapeutic follow-up. One of the most promising sources of biomarkers is represented by extracellular vesicles (EVs), a heterogeneous population of nanoparticles, released by all cells in the microenvironment. Brain-derived EVs are able to cross the blood-brain barrier, protecting their payload from enzymatic degradation, and are easily recovered from biofluids. Interestingly, EV content is strongly influenced by the specific pathophysiological status of the donor cell. In this manuscript, the role of EVs as source of novel PD biomarkers is discussed, providing all recent findings concerning relevant proteins and miRNAs carried by PD patient-derived EVs, from several biological specimens. Moreover, the contribution of mitochondria-derived EVs will be dissected. Finally, the promising possibility to use EVs as source of markers to monitor PD therapy efficacy will be also examined. In the future, larger cohort studies will help to validate these EV-associated candidates, that might be effectively used as non-invasive and robust source of biomarkers for PD.

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α-Synuclein in blood exosomes immunoprecipitated using neuronal and oligodendroglial markers distinguishes Parkinson’s disease from multiple system atrophy

Cited by 106 publications

References 71 publications

Plasma Small Extracellular Vesicles with Complement Alterations in GRN/C9orf72 and Sporadic Frontotemporal Lobar Degeneration

Plasma Small Extracellular Vesicles with Complement Alterations in GRN/C9orf72 and Sporadic Frontotemporal Lobar Degeneration

The Concept of α-Synuclein Strains and How Different Conformations May Explain Distinct Neurodegenerative Disorders

Extracellular Vesicles as Novel Diagnostic and Prognostic Biomarkers for Parkinson’s Disease

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