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Small Extracellular Vesicles Secreted by Region-specific Astrocytes Ameliorate the Mitochondrial Function in a Cellular Model of Parkinson’s Disease

Loredana Leggio, Francesca L’Episcopo, Andrea Magrì, María José Ulloa-Navas, Greta Paternò, Silvia Vivarelli, Carlos A. P. Bastos, Cataldo Tirolo, Nunzio Testa, Salvatore Caniglia, Pierpaolo Risiglione, Fabrizio Pappalardo, Nuno Faria, Luca Peruzzotti-Jametti, Stefano Pluchino, José Manuel García-Verdugo, Angela Messina, Bianca Marchetti, View ORCID ProfileNunzio Iraci
doi: https://doi.org/10.1101/2021.04.23.441135
Loredana Leggio
1Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, 95123, Italy
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Francesca L’Episcopo
2Oasi Research Institute-IRCCS, Troina, 94018, Italy
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Andrea Magrì
3Department of Biological, Geological and Environmental Sciences, University of Catania, Catania, 95125, Italy
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María José Ulloa-Navas
4Laboratory of Compared Neurobiology, University of Valencia-CIBERNED, Paterna, 46980, Spain
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Greta Paternò
1Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, 95123, Italy
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Silvia Vivarelli
1Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, 95123, Italy
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Carlos A. P. Bastos
5Department of Veterinary Medicine, University of Cambridge, Cambridge, CB3 0ES, United Kingdom
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Cataldo Tirolo
2Oasi Research Institute-IRCCS, Troina, 94018, Italy
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Nunzio Testa
2Oasi Research Institute-IRCCS, Troina, 94018, Italy
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Salvatore Caniglia
2Oasi Research Institute-IRCCS, Troina, 94018, Italy
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Pierpaolo Risiglione
3Department of Biological, Geological and Environmental Sciences, University of Catania, Catania, 95125, Italy
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Fabrizio Pappalardo
1Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, 95123, Italy
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Nuno Faria
5Department of Veterinary Medicine, University of Cambridge, Cambridge, CB3 0ES, United Kingdom
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Luca Peruzzotti-Jametti
6Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom
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Stefano Pluchino
6Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom
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José Manuel García-Verdugo
4Laboratory of Compared Neurobiology, University of Valencia-CIBERNED, Paterna, 46980, Spain
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Angela Messina
3Department of Biological, Geological and Environmental Sciences, University of Catania, Catania, 95125, Italy
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Bianca Marchetti
1Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, 95123, Italy
2Oasi Research Institute-IRCCS, Troina, 94018, Italy
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  • For correspondence: biancamarchetti@libero.it nunzio.iraci@unict.it
Nunzio Iraci
1Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, 95123, Italy
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  • ORCID record for Nunzio Iraci
  • For correspondence: biancamarchetti@libero.it nunzio.iraci@unict.it
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Abstract

Extracellular vesicles (EVs) are emerging as powerful players in cell-to-cell communication both in health and diseased brain. In Parkinson’s disease (PD) – characterized by selective dopaminergic (DAergic) neuron death in ventral midbrain (VMB) and degeneration of DAergic terminals in striatum (STR) – astrocytes (AS) exert dual harmful/protective functions. When activated by chemokine CCL3, AS promote a robust DAergic neuroprotection both in cellular and pre-clinical models of PD, with mechanisms not fully elucidated. Here we used a combination of techniques to characterize AS-EVs derived from VMB and STR, and investigated their potential to exert neuroprotection. First, we show that: (i) AS of both regions secrete small EVs of ~100 nm; (ii) VMB-AS release more EVs per cell than STR-AS under basal conditions; and (iii) only VMB-AS respond to CCL3 by producing more EVs, suggesting differential AS-EV secretion rate according to PD brain region. Next, addressing AS-EV potential against oxidative stress and mitochondrial toxicity, we found that AS-EVs, especially CCL3-AS-EVs, fully counteract H2O2-induced caspase-3 activation. Furthermore, using high resolution respirometry, we demonstrated that AS-EVs rescue the neuronal mitochondrial complex I function impaired by MPP+, with VMB-AS-EVs fully restoring ATP production in MPP+-injured neurons, highlighting a regional diversity of AS-EVs with neuroprotective implications for PD.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵# Co-last authors

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Small Extracellular Vesicles Secreted by Region-specific Astrocytes Ameliorate the Mitochondrial Function in a Cellular Model of Parkinson’s Disease
Loredana Leggio, Francesca L’Episcopo, Andrea Magrì, María José Ulloa-Navas, Greta Paternò, Silvia Vivarelli, Carlos A. P. Bastos, Cataldo Tirolo, Nunzio Testa, Salvatore Caniglia, Pierpaolo Risiglione, Fabrizio Pappalardo, Nuno Faria, Luca Peruzzotti-Jametti, Stefano Pluchino, José Manuel García-Verdugo, Angela Messina, Bianca Marchetti, Nunzio Iraci
bioRxiv 2021.04.23.441135; doi: https://doi.org/10.1101/2021.04.23.441135
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Small Extracellular Vesicles Secreted by Region-specific Astrocytes Ameliorate the Mitochondrial Function in a Cellular Model of Parkinson’s Disease
Loredana Leggio, Francesca L’Episcopo, Andrea Magrì, María José Ulloa-Navas, Greta Paternò, Silvia Vivarelli, Carlos A. P. Bastos, Cataldo Tirolo, Nunzio Testa, Salvatore Caniglia, Pierpaolo Risiglione, Fabrizio Pappalardo, Nuno Faria, Luca Peruzzotti-Jametti, Stefano Pluchino, José Manuel García-Verdugo, Angela Messina, Bianca Marchetti, Nunzio Iraci
bioRxiv 2021.04.23.441135; doi: https://doi.org/10.1101/2021.04.23.441135

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