TY - JOUR T1 - Small Extracellular Vesicles Secreted by Region-specific Astrocytes Ameliorate the Mitochondrial Function in a Cellular Model of Parkinson’s Disease JF - bioRxiv DO - 10.1101/2021.04.23.441135 SP - 2021.04.23.441135 AU - Loredana Leggio AU - Francesca L’Episcopo AU - Andrea Magrì AU - María José Ulloa-Navas AU - Greta Paternò AU - Silvia Vivarelli AU - Carlos A. P. Bastos AU - Cataldo Tirolo AU - Nunzio Testa AU - Salvatore Caniglia AU - Pierpaolo Risiglione AU - Fabrizio Pappalardo AU - Nuno Faria AU - Luca Peruzzotti-Jametti AU - Stefano Pluchino AU - José Manuel García-Verdugo AU - Angela Messina AU - Bianca Marchetti AU - Nunzio Iraci Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/04/23/2021.04.23.441135.abstract N2 - 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 StatementThe authors have declared no competing interest. ER -