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The impact of hUC MSC-derived exosome-nanoliposome hybrids on α-synuclein fibrillation and neurotoxicity.

ABSTRACT: Amyloid aggregation of α-synuclein (αSN) protein amplifies the pathogenesis of neurodegenerative diseases (NDs) such as Parkinson's disease (PD). Consequently, blocking aggregation or redirecting self-assembly to less toxic aggregates could be therapeutic. Here, we improve brain-specific nanocarriers using a hybrid of exosomes (Ex) from human umbilical cord mesenchymal stem cells (hUC MSCs) and nanoliposomes containing baicalein (Ex-NLP-Ba) and oleuropein (Ex-NLP-Ole). The hybrids contained both lipid membranes, Ex proteins, and baicalein or oleuropein. Fluorescence resonance energy transfer analysis confirmed their proper integration. The hybrids reduced the extent of αSN fibrillation and interfered with secondary nucleation and disaggregation. They not only reduced αSN pathogenicity but also enhanced drug internalization into cells, surpassing the efficacy of NLP alone, and also crossed the blood-brain barrier in a cellular model. We conclude that Ex can be successfully extracted and efficiently merged with NLPs while retaining its original properties, demonstrating great potential as a theranostic drug delivery vehicle against NDs like PD.

SUBMITTER: Aliakbari F

PROVIDER: S-EPMC10990263 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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The impact of hUC MSC-derived exosome-nanoliposome hybrids on α-synuclein fibrillation and neurotoxicity.

Aliakbari Farhang F Marzookian Kimia K Parsafar Soha S Hourfar Hamdam H Nayeri Zahra Z Fattahi Arghavan A Raeiji Mohammad M Boroujeni Narges Nasrollahi NN Otzen Daniel E DE Morshedi Dina D

Science advances 20240403 14

Amyloid aggregation of α-synuclein (αSN) protein amplifies the pathogenesis of neurodegenerative diseases (NDs) such as Parkinson's disease (PD). Consequently, blocking aggregation or redirecting self-assembly to less toxic aggregates could be therapeutic. Here, we improve brain-specific nanocarriers using a hybrid of exosomes (Ex) from human umbilical cord mesenchymal stem cells (hUC MSCs) and nanoliposomes containing baicalein (Ex-NLP-Ba) and oleuropein (Ex-NLP-Ole). The hybrids contained both ...[more]

PMID: 38569030

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Project description:BackgroundSynucleinopathies, including Parkinson's disease (PD), are characterized by α-synuclein (αS) cytoplasmic inclusions. αS-dependent vesicle-trafficking defects are important in PD pathogenesis, but their mechanisms are not well understood. Protein palmitoylation, post-translational addition of the fatty acid palmitate to cysteines, promotes trafficking by anchoring specific proteins to the vesicle membrane. αS itself cannot be palmitoylated as it lacks cysteines, but it binds to membranes, where palmitoylation occurs, via an amphipathic helix. We hypothesized that abnormal αS membrane-binding impairs trafficking by disrupting palmitoylation. Accordingly, we investigated the therapeutic potential of increasing cellular palmitoylation.ObjectivesWe asked whether upregulating palmitoylation by inhibiting the depalmitoylase acyl-protein-thioesterase-1 (APT1) ameliorates pathologic αS-mediated cellular phenotypes and sought to identify the mechanism.MethodsUsing human neuroblastoma cells, rat neurons, and iPSC-derived PD patient neurons, we examined the effects of pharmacologic and genetic downregulation of APT1 on αS-associated phenotypes.ResultsAPT1 inhibition or knockdown decreased αS cytoplasmic inclusions, reduced αS serine-129 phosphorylation (a PD neuropathological marker), and protected against αS-dependent neurotoxicity. We identified the APT1 substrate microtubule-associated-protein-6 (MAP6), which binds to vesicles in a palmitoylation-dependent manner, as a key mediator of these effects. Mechanistically, we found that pathologic αS accelerated palmitate turnover on MAP6, suggesting that APT1 inhibition corrects a pathological αS-dependent palmitoylation deficit. We confirmed the disease relevance of this mechanism by demonstrating decreased MAP6 palmitoylation in neurons from αS gene triplication patients.ConclusionsOur findings demonstrate a novel link between the fundamental process of palmitoylation and αS pathophysiology. Upregulating palmitoylation represents an unexplored therapeutic strategy for synucleinopathies. © 2020 International Parkinson and Movement Disorder Society.

Dataset Information

The impact of hUC MSC-derived exosome-nanoliposome hybrids on α-synuclein fibrillation and neurotoxicity.

Publications

The impact of hUC MSC-derived exosome-nanoliposome hybrids on α-synuclein fibrillation and neurotoxicity.

Similar Datasets

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