Oligomeric α-Syn and SNARE complex proteins in peripheral extracellular vesicles of neural origin are biomarkers for Parkinson's disease

Agliardi, Cristina; Meloni, Mario; Guerini, Franca Rosa; Zanzottera, Milena; Bolognesi, Elisabetta; Baglio, Francesca; Clerici, Mario

doi:10.1016/j.nbd.2020.105185

Cited by 89 publications

(88 citation statements)

References 54 publications

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“…The latter regulates synaptic functions and plasticity, interacting with the SNARE proteins that mediate the docking of neurotransmitter vesicles, exocytosis, and neurotransmitter release [ 56 ]. Thus, PD neurodegeneration initiates as a synaptopathy [ 57 ], and postmortem PD brains exhibit an altered balance of the SNARE proteins [ 58 ], which are sequestered within LBs [ 57 ]., The progression of degeneration leads to the reduced expression of genes involved in SNARE complex formation [ 59 ]. Upon treatment with fibrils, we observed a reduced expression of genes coding for SNARE complex (SYP and VAMP2) proteins, for the monoamine SLC vesicular transporters VMAT2, and for the dopamine transporter DAT.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Ceramide Synthesis Reduces α-Synuclein Proteinopathy in a Cellular Model of Parkinson’s Disease

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Pivari

Plotegher

et al. 2021

IJMS

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Parkinson’s disease (PD) is a proteinopathy associated with the aggregation of α-synuclein and the formation of lipid–protein cellular inclusions, named Lewy bodies (LBs). LB formation results in impaired neurotransmitter release and uptake, which involve membrane traffic and require lipid synthesis and metabolism. Lipids, particularly ceramides, are accumulated in postmortem PD brains and altered in the plasma of PD patients. Autophagy is impaired in PD, reducing the ability of neurons to clear protein aggregates, thus worsening stress conditions and inducing neuronal death. The inhibition of ceramide synthesis by myriocin (Myr) in SH-SY5Y neuronal cells treated with preformed α-synuclein fibrils reduced intracellular aggregates, favoring their sequestration into lysosomes. This was associated with TFEB activation, increased expression of TFEB and LAMP2, and the cytosolic accumulation of LC3II, indicating that Myr promotes autophagy. Myr significantly reduces the fibril-related production of inflammatory mediators and lipid peroxidation and activates NRF2, which is downregulated in PD. Finally, Myr enhances the expression of genes that control neurotransmitter transport (SNARE complex, VMAT2, and DAT), whose progressive deficiency occurs in PD neurodegeneration. The present study suggests that counteracting the accumulation of inflammatory lipids could represent a possible therapeutic strategy for PD.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Ceramide Synthesis Reduces α-Synuclein Proteinopathy in a Cellular Model of Parkinson’s Disease

Mingione

Pivari

Plotegher

et al. 2021

IJMS

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“…Thus, our strategy to recalibrate the model on EV surface markers that were expressed both in plasma and CSF in each diagnostic group allowed us to improve the diagnostic system that remains based on EV profiling in plasma. This is a novel approach to blood biomarkers by profiling EV surface markers related to inflammatory and immune cells with potential roles in inflammation related to neurodegeneration, while most of the current studies on EVs as biomarkers are focused especially on evaluating target proteins in neuronal-derived exosomes [24,25]. Further, the multiplexed profiling of inflammation markers allows a more personalized approach, as this biomarker-driven phenotyping might be capable of capturing the clinical heterogeneity of PD and may be used to measure the effect of potential disease-modifying drugs on peripheral inflammatory processes as a proxy for central events.…”

Section: Discussionmentioning

confidence: 99%

Profiling Inflammatory Extracellular Vesicles in Plasma and Cerebrospinal Fluid: An Optimized Diagnostic Model for Parkinson’s Disease

Vacchi

Burrello

et al. 2021

Biomedicines

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Extracellular vesicles (EVs) play a central role in intercellular communication, which is relevant for inflammatory and immune processes implicated in neurodegenerative disorders, such as Parkinson’s Disease (PD). We characterized and compared distinctive cerebrospinal fluid (CSF)-derived EVs in PD and atypical parkinsonisms (AP), aiming to integrate a diagnostic model based on immune profiling of plasma-derived EVs via artificial intelligence. Plasma- and CSF-derived EVs were isolated from patients with PD, multiple system atrophy (MSA), AP with tauopathies (AP-Tau), and healthy controls. Expression levels of 37 EV surface markers were measured by a flow cytometric bead-based platform and a diagnostic model based on expression of EV surface markers was built by supervised learning algorithms. The PD group showed higher amount of CSF-derived EVs than other groups. Among the 17 EV surface markers differentially expressed in plasma, eight were expressed also in CSF of a subgroup of PD, 10 in MSA, and 6 in AP-Tau. A two-level random forest model was built using EV markers co-expressed in plasma and CSF. The model discriminated PD from non-PD patients with high sensitivity (96.6%) and accuracy (92.6%). EV surface marker characterization bolsters the relevance of inflammation in PD and it underscores the role of EVs as pathways/biomarkers for protein aggregation-related neurodegenerative diseases.

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“…It has been hypothesized that neurodegeneration begins with alterations at the synaptic terminals in the striatum and then it progresses along the nigrostriatal pathway causing degeneration of the dopaminergic neurons, therefore PD can be classified as a synapthopathy [ 55 ]. Besides synuclein toxicity and oxidative stress also neuroinflammation, mitochondrial dysfunction, lysosomal impairment, endoplasmic reticulum stress, synaptic dysfunction and contribution of glial cells are responsible for apoptosis and progression of the disease [ 79 ].…”

Section: Pdmentioning

confidence: 99%

“…Intriguingly, YKT6 is extremely abundant in neurons and in the dopaminergic PC12 cell line where it can be found in specific cytoplasmic particles [ 94 , 95 ]. EVs containing oligomers of α-syn were abundant in peripheral blood from PD patients while syntaxin-1a and VAMP2 levels were reduced [ 55 ]. Interestingly, SNAP-25 was increased in CSF of PD patients and different single-nucleotide polymorphisms (SNPs) have been associated with the pathogenesis of PD [ 61 ].…”

Section: Pdmentioning

confidence: 99%

Role of SNAREs in Neurodegenerative Diseases

Margiotta

2021

Cells

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Neurodegenerative diseases are pathologies of the central and peripheral nervous systems characterized by loss of brain functions and problems in movement which occur due to the slow and progressive degeneration of cellular elements. Several neurodegenerative diseases are known such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis and many studies on the molecular mechanisms underlying these pathologies have been conducted. Altered functions of some key proteins and the presence of intraneuronal aggregates have been identified as responsible for the development of the diseases. Interestingly, the formation of the SNARE complex has been discovered to be fundamental for vesicle fusion, vesicle recycling and neurotransmitter release. Indeed, inhibition of the formation of the SNARE complex, defects in the SNARE-dependent exocytosis and altered regulation of SNARE-mediated vesicle fusion have been associated with neurodegeneration. In this review, the biological aspects of neurodegenerative diseases and the role of SNARE proteins in relation to the onset of these pathologies are described.

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Oligomeric α-Syn and SNARE complex proteins in peripheral extracellular vesicles of neural origin are biomarkers for Parkinson's disease

Cited by 89 publications

References 54 publications

Inhibition of Ceramide Synthesis Reduces α-Synuclein Proteinopathy in a Cellular Model of Parkinson’s Disease

Inhibition of Ceramide Synthesis Reduces α-Synuclein Proteinopathy in a Cellular Model of Parkinson’s Disease

Profiling Inflammatory Extracellular Vesicles in Plasma and Cerebrospinal Fluid: An Optimized Diagnostic Model for Parkinson’s Disease

Role of SNAREs in Neurodegenerative Diseases

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