Small Extracellular Vesicles Secreted by Nigrostriatal Astrocytes Rescue Cell Death and Preserve Mitochondrial Function in Parkinson's Disease

Extracellular vesicles (EVs) are emerging as powerful players in cell‐to‐cell communication both in healthy and diseased brain. In Parkinson's disease (PD)—characterized by selective dopaminergic neuron death in ventral midbrain (VMB) and degeneration of their terminals in striatum (STR)—astroc...

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Published in:Advanced healthcare materials 2022-10, Vol.11 (20), p.e2201203-n/a
Main Authors: Leggio, Loredana, L'Episcopo, Francesca, Magrì, Andrea, Ulloa‐Navas, María José, Paternò, Greta, Vivarelli, Silvia, Bastos, Carlos A. P., Tirolo, Cataldo, Testa, Nunzio, Caniglia, Salvatore, Risiglione, Pierpaolo, Pappalardo, Fabrizio, Serra, Alessandro, García‐Tárraga, Patricia, Faria, Nuno, Powell, Jonathan J., Peruzzotti‐Jametti, Luca, Pluchino, Stefano, García‐Verdugo, José Manuel, Messina, Angela, Marchetti, Bianca, Iraci, Nunzio
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - metabolism
Astrocytes
Astrocytes - metabolism
Caspase
Caspase 3 - metabolism
CCL3 protein
Cell activation
Cell Death
Cell differentiation
Cell interactions
Chemokines
Degeneration
Dopamine - pharmacology
Dopamine receptors
Dopaminergic Neurons - metabolism
Electron transport chain
exosomes
Extracellular vesicles
Extracellular Vesicles - metabolism
high‐resolution respirometry
Humans
Hydrogen peroxide
Mesencephalon
Mitochondria
Movement disorders
MPP
NADH-ubiquinone oxidoreductase
Neostriatum
Neuroblastoma - metabolism
Neurodegeneration
Neurodegenerative diseases
Neuroprotection
Neurotoxicity
Neurotoxins - metabolism
Neurotoxins - pharmacology
Oxidative stress
Parkinson Disease - metabolism
Parkinson's disease
Respirometry
Toxicity
Toxins
Vesicles
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Summary:Extracellular vesicles (EVs) are emerging as powerful players in cell‐to‐cell communication both in healthy and diseased brain. In Parkinson's disease (PD)—characterized by selective dopaminergic neuron death in ventral midbrain (VMB) and degeneration of their terminals in striatum (STR)—astrocytes exert dual harmful/protective functions, with mechanisms not fully elucidated. Here, this study shows that astrocytes from the VMB‐, STR‐, and VMB/STR‐depleted brains release a population of small EVs  in a region‐specific manner. Interestingly, VMB‐astrocytes secreted the highest rate of EVs, which is further exclusively increased in response to CCL3, a chemokine that promotes robust dopaminergic neuroprotection in different PD models. The neuroprotective potential of nigrostriatal astrocyte‐EVs is investigated in differentiated versus undifferentiated SH‐SY5Y cells exposed to oxidative stress and mitochondrial toxicity. EVs from both VMB‐ and STR‐astrocytes counteract H2O2‐induced caspase‐3 activation specifically in differentiated cells, with EVs from CCL3‐treated astrocytes showing a higher protective effect. High resolution respirometry further reveals that nigrostriatal astrocyte‐EVs rescue neuronal mitochondrial complex I function impaired by the neurotoxin MPP+. Notably, only EVs from VMB‐astrocyte fully restore ATP production, again specifically in differentiated SH‐SY5Y. These results highlight a regional diversity in the nigrostriatal system for the secretion and activities of astrocyte‐EVs, with neuroprotective implications for PD. Astrocytes from the main brain regions affected by Parkinson's disease (PD) secrete different levels of extracellular vesicles (EVs). CCL3‐EVs better protect neurons from apoptosis and only ventral midbrain‐derived EVs ameliorate ATP production in neurotoxin‐injured neurons. These data demonstrate the importance of the brain region for the neuroprotection mediated by astrocyte‐EVs, with implications for PD diagnosis and treatment.
ISSN:2192-2640
2192-2659
DOI:10.1002/adhm.202201203