Exosomes in Alpha-Synucleinopathies: Propagators of Pathology or Potential Candidates for Nanotherapeutics?

Mavroeidi, Panagiota; Vetsi, Maria; Dionysopoulou, Dimitra; Xilouri, Maria

doi:10.3390/biom12070957

Cited by 19 publications

(12 citation statements)

References 173 publications

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“…Neurons and glial cells can release exosomes that can be found in blood plasma and cerebrospinal fluid. Exosomes could be a way of allowing altered α‐syn out of the intracellular compartment (Hasegawa et al, 2017; Mavroeidi et al, 2022; Stefanis et al, 2019). CNS‐derived extracellular vesicles derived from PD patients contain SNARE proteins and toxic forms of α‐syn (Agliardi et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

The Golgi complex of dopaminergic enteric neurons is fragmented in a hemiparkinsonian rat model

Cara‐Esteban,

Marín,

Martínez‐Alonso

et al. 2023

Microscopy Res & Technique

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Since gastrointestinal disorders are early consequences of Parkinson's disease (PD), this disease is clearly not restricted to the central nervous system (CNS), but also significantly affects the enteric nervous system (ENS). Large aggregates of the protein α‐synuclein forming Lewy bodies, the prototypical cytopathological marker of this disease, have been observed in enteric nervous plexuses. However, their value in early prognosis is controversial. The Golgi complex (GC) of nigral neurons appears fragmented in Parkinson's disease, a characteristic common in most neurodegenerative diseases. In addition, the distribution and levels of regulatory proteins such as Rabs and SNAREs are altered, suggesting that PD is a membrane traffic‐related pathology. Whether the GC of enteric dopaminergic neurons is affected by the disease has not yet been analyzed. In the present study, dopaminergic neurons in colon nervous plexuses behave as nigral neurons in a hemiparkinsonian rat model based on the injection of the toxin 6‐OHDA. Their GCs are fragmented, and some regulatory proteins' distribution and expression levels are altered. The putative mechanisms of the transmission of the neurotoxin to the ENS are discussed. Our results support the possibility that GC structure and the level of some proteins, especially syntaxin 5, could be helpful as early indicators of the disease.Research Highlights The Golgi complexes of enteric dopaminergic neurons appear fragmented in a Parkinson's disease rat model. Our results support the hypothesis that the Golgi complex structure and levels of Rab1 and syntaxin 5 could be helpful as early indicators of the disease.

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Section: Discussionmentioning

confidence: 99%

The Golgi complex of dopaminergic enteric neurons is fragmented in a hemiparkinsonian rat model

Cara‐Esteban,

Marín,

Martínez‐Alonso

et al. 2023

Microscopy Res & Technique

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“…Two independent researchers (HBT and SSA) screened all the titles, abstracts, and full manuscripts to select articles that met the eligibility criteria. By hand, we reviewed the reference lists of eligible studies, searched Google scholar for articles measuring α‐syn in CNS‐originating EVs and detailed reviews of the literature for inclusion of eligible studies 29‐35 . Any discrepancies in article selection were resolved through discussion.…”

Section: Methodsmentioning

confidence: 99%

“…By hand, we reviewed the reference lists of eligible studies, searched Google scholar for articles measuring α-syn in CNSoriginating EVs and detailed reviews of the literature for inclusion of eligible studies. [29][30][31][32][33][34][35] Any discrepancies in article selection were resolved through discussion. The complete search strategy can be found in Table S1.…”

Section: Datasourcesandsearchstrategymentioning

confidence: 99%

Evaluation of α‐synuclein in CNS‐originating extracellular vesicles for Parkinsonian disorders: A systematic review and meta‐analysis

Taha

Ati

2023

CNS Neurosci Ther

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Background & AimsParkinsonian disorders, such as Parkinson's disease (PD), multiple system atrophy (MSA), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), share early motor symptoms but have distinct pathophysiology. As a result, accurate premortem diagnosis is challenging for neurologists, hindering efforts for disease‐modifying therapeutic discovery. Extracellular vesicles (EVs) contain cell‐state‐specific biomolecules and can cross the blood‐brain barrier to the peripheral circulation, providing a unique central nervous system (CNS) insight. This meta‐analysis evaluated blood‐isolated neuronal and oligodendroglial EVs (nEVs and oEVs) α‐synuclein levels in Parkinsonian disorders.MethodsFollowing PRISMA guidelines, the meta‐analysis included 13 studies. An inverse‐variance random‐effects model quantified effect size (SMD), QUADAS‐2 assessed risk of bias and publication bias was evaluated. Demographic and clinical variables were collected for meta‐regression.ResultsThe meta‐analysis included 1,565 patients with PD, 206 with MSA, 21 with DLB, 172 with PSP, 152 with CBS and 967 healthy controls (HCs). Findings suggest that combined concentrations of nEVs and oEVs α‐syn is higher in patients with PD compared to HCs (SMD = 0.21, p = 0.021), while nEVs α‐syn is lower in patients with PSP and CBS compared to patients with PD (SMD = ‐1.04, p = 0.0017) or HCs (SMD = ‐0.41, p < 0.001). Additionally, α‐syn in nEVs and/or oEVs did not significantly differ in patients with PD vs. MSA, contradicting the literature. Meta‐regressions show that demographic and clinical factors were not significant predictors of nEVs or oEVs α‐syn concentrations.ConclusionThe results highlight the need for standardized procedures and independent validations in biomarker studies and the development of improved biomarkers for distinguishing Parkinsonian disorders.

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“…Exosomes are considered to be transporters of toxic α-synuclein oligomers. Both neurons and glial cells can release exosomes, which may contain inflammatory molecules and this glia-to-neuron or neuron-to-glia transmission of exosomal α-synuclein oligomers may contribute to the propagation of pathology and neuroinflammation throughout the brain in MSA [ 52 ].…”

Section: Neuropathologymentioning

confidence: 99%

Multiple system atrophy: an update and emerging directions of biomarkers and clinical trials

Liu,

Wang,

Shang

2024

J Neurol

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Multiple system atrophy is a rare, debilitating, adult-onset neurodegenerative disorder that manifests clinically as a diverse combination of parkinsonism, cerebellar ataxia, and autonomic dysfunction. It is pathologically characterized by oligodendroglial cytoplasmic inclusions containing abnormally aggregated α-synuclein. According to the updated Movement Disorder Society diagnostic criteria for multiple system atrophy, the diagnosis of clinically established multiple system atrophy requires the manifestation of autonomic dysfunction in combination with poorly levo-dopa responsive parkinsonism and/or cerebellar syndrome. Although symptomatic management of multiple system atrophy can substantially improve quality of life, therapeutic benefits are often limited, ephemeral, and they fail to modify the disease progression and eradicate underlying causes. Consequently, effective breakthrough treatments that target the causes of disease are needed. Numerous preclinical and clinical studies are currently focusing on a set of hallmarks of neurodegenerative diseases to slow or halt the progression of multiple system atrophy: pathological protein aggregation, synaptic dysfunction, aberrant proteostasis, neuronal inflammation, and neuronal cell death. Meanwhile, specific biomarkers and measurements with higher specificity and sensitivity are being developed for the diagnosis of multiple system atrophy, particularly for early detection of the disease. More intriguingly, a growing number of new disease-modifying candidates, which can be used to design multi-targeted, personalized treatment in patients, are being investigated, notwithstanding the failure of most previous attempts.

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Exosomes in Alpha-Synucleinopathies: Propagators of Pathology or Potential Candidates for Nanotherapeutics?

Cited by 19 publications

References 173 publications

The Golgi complex of dopaminergic enteric neurons is fragmented in a hemiparkinsonian rat model

The Golgi complex of dopaminergic enteric neurons is fragmented in a hemiparkinsonian rat model

Evaluation of α‐synuclein in CNS‐originating extracellular vesicles for Parkinsonian disorders: A systematic review and meta‐analysis

Multiple system atrophy: an update and emerging directions of biomarkers and clinical trials

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