4.7 Article

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

Journal

ADVANCED HEALTHCARE MATERIALS
Volume 11, Issue 20, Pages -

Publisher

WILEY
DOI: 10.1002/adhm.202201203

Keywords

astrocytes; exosomes; extracellular vesicles; high-resolution respirometry; mitochondria; Parkinson's disease

Funding

  1. Italian Ministry for Education, University and Research (MIUR) [PONa3_00136]
  2. Brain to South grant (Fondazione con il Sud - Bando Capitale Umano ad Alta Qualificazione 2015)
  3. Italian Ministry of Health
  4. University of Catania
  5. AIM Linea 1 Salute [AIM1833071]
  6. Spanish Ministry of Science, Innovation and Universities [PCI2018-093062]
  7. Red de Terapia Celular [TerCel-RD16/0011/0026]
  8. universita degli Studi di Catania within the CRUI-CARE agreement

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Extracellular vesicles released by astrocytes in the brain of Parkinson's disease patients play a significant role in cell-to-cell communication and have neuroprotective effects on dopaminergic neurons. Nigrostriatal astrocytes release the highest number of EVs, especially in response to CCL3, which promotes dopaminergic neuroprotection. These EVs specifically protect differentiated cells from oxidative stress-induced caspase-3 activation and restore impaired mitochondrial function caused by the neurotoxin MPP+. EVs from VMB-astrocytes fully restore ATP production in differentiated SH-SY5Y cells.
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.

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