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Small Extracellular Vesicles Secreted by Nigrostriatal Astrocytes Rescue Cell Death and Preserve Mitochondrial Function in Parkinson's Disease
Author(s) -
Leggio Loredana,
L'Episcopo Francesca,
Magrì Andrea,
UlloaNavas María José,
Paternò Greta,
Vivarelli Silvia,
Bastos Carlos A. P.,
Tirolo Cataldo,
Testa Nunzio,
Caniglia Salvatore,
Risiglione Pierpaolo,
Pappalardo Fabrizio,
Serra Alessandro,
GarcíaTárraga Patricia,
Faria Nuno,
Powell Jonathan J.,
PeruzzottiJametti Luca,
Pluchino Stefano,
GarcíaVerdugo José Manuel,
Messina Angela,
Marchetti Bianca,
Iraci Nunzio
Publication year - 2022
Publication title -
advanced healthcare materials
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.288
H-Index - 90
eISSN - 2192-2659
pISSN - 2192-2640
DOI - 10.1002/adhm.202201203
Subject(s) - neuroprotection , astrocyte , dopaminergic , neurodegeneration , biology , microbiology and biotechnology , parkinson's disease , striatum , oxidative stress , neuroinflammation , neuroscience , chemistry , dopamine , medicine , central nervous system , immunology , endocrinology , inflammation , 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)—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 H 2 O 2 ‐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.