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

Leggio, L.; L'Episcopo, F.; Magri', A.; Ulloa-Navas, M. J.; Paterno', G.; Vivarelli, S.; Bastos, C. A. P.; Tirolo, C.; Testa, N.; Caniglia, S.; Risiglione, P.; Pappalardo, F.; Faria, N.; Peruzzotti-Jametti, L.; Pluchino, S.; Garcia-Verdugo, J. M.; Messina, A.; Marchetti, B.; Iraci, N.

doi:10.1101/2021.04.23.441135

bioRxiv · 10.1101/2021.04.23.441135

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

Leggio, L.·L'Episcopo, F.·Magri', A.·Ulloa-Navas, M. J.·Paterno', G.·Vivarelli, S.·Bastos, C. A. P.·Tirolo, C.·Testa, N.·Caniglia, S.·Risiglione, P.·Pappalardo, F.·Faria, N.·Peruzzotti-Jametti, L.·Pluchino, S.·Garcia-Verdugo, J. M.·Messina, A.·Marchetti, B.·Iraci, N.

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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 Parkinsons 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.

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Leggio, L., L'Episcopo, F., Magri', A., Ulloa-Navas, M. J., Paterno', G., Vivarelli, S., Bastos, C. A. P., Tirolo, C., Testa, N., Caniglia, S., Risiglione, P., Pappalardo, F., Faria, N., Peruzzotti-Jametti, L., Pluchino, S., Garcia-Verdugo, J. M., Messina, A., Marchetti, B., Iraci, N.. 2021-04-23. Small Extracellular Vesicles Secreted by Region-specific Astrocytes Ameliorate the Mitochondrial Function in a Cellular Model of Parkinson's Disease. https://doi.org/10.1101/2021.04.23.441135

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