Mitochondrial damage by α-synuclein causes cell death in human dopaminergic neurons

Cell Death Dis. 2019 Nov 14;10(11):865. doi: 10.1038/s41419-019-2091-2.

Ganjam GK1,2,3, Bolte K4, Matschke LA5, Neitemeier S6, Dolga AM6,7, Höllerhage M8, Höglinger GU8, Adamczyk A9, Decher N5, Oertel WH10,11, Culmsee C6,11,12.


Author information

  1. Institute for Pharmacology and Clinical Pharmacy, Biochemical-Pharmacological Center, University of Marburg, Marburg, Germany. Ten adres pocztowy jest chroniony przed spamowaniem. Aby go zobaczyć, konieczne jest włączenie w przeglądarce obsługi JavaScript..
  2. Department of Neurology, University of Marburg, Marburg, Germany. Ten adres pocztowy jest chroniony przed spamowaniem. Aby go zobaczyć, konieczne jest włączenie w przeglądarce obsługi JavaScript..
  3. Center for Mind, Brain and Behaviour - CMBB, Marburg, Germany. Ten adres pocztowy jest chroniony przed spamowaniem. Aby go zobaczyć, konieczne jest włączenie w przeglądarce obsługi JavaScript..
  4. Laboratory for Cell Biology I, Department of Biology, University of Marburg, Marburg, Germany.
  5. Institute of Physiology and Pathophysiology, University of Marburg, Marburg, Germany.
  6. Institute for Pharmacology and Clinical Pharmacy, Biochemical-Pharmacological Center, University of Marburg, Marburg, Germany.
  7. Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands.
  8. German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
  9. Department of Cellular Signaling, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.
  10. Department of Neurology, University of Marburg, Marburg, Germany.
  11. Center for Mind, Brain and Behaviour - CMBB, Marburg, Germany.
  12. Department of Pediatrics, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

Abstract

Evolving concepts on Parkinson's disease (PD) pathology suggest that α-synuclein (aSYN) promote dopaminergic neuron dysfunction and death through accumulating in the mitochondria. However, the consequence of mitochondrial aSYN localisation on mitochondrial structure and bioenergetic functions in neuronal cells are poorly understood. Therefore, we investigated deleterious effects of mitochondria-targeted aSYN in differentiated human dopaminergic neurons in comparison with wild-type (WT) aSYN overexpression and corresponding EGFP (enhanced green fluorescent protein)-expressing controls. Mitochondria-targeted aSYN enhanced mitochondrial reactive oxygen species (ROS) formation, reduced ATP levels and showed severely disrupted structure and function of the dendritic neural network, preceding neuronal death. Transmission electron microscopy illustrated distorted cristae and many fragmented mitochondria in response to WT-aSYN overexpression, and a complete loss of cristae structure and massively swollen mitochondria in neurons expressing mitochondria-targeted aSYN. Further, the analysis of mitochondrial bioenergetics in differentiated dopaminergic neurons, expressing WT or mitochondria-targeted aSYN, elicited a pronounced impairment of mitochondrial respiration. In a pharmacological compound screening, we found that the pan-caspase inhibitors QVD and zVAD-FMK, and a specific caspase-1 inhibitor significantly prevented aSYN-induced cell death. In addition, the caspase inhibitor QVD preserved mitochondrial function and neuronal network activity in the human dopaminergic neurons overexpressing aSYN. Overall, our findings indicated therapeutic effects by caspase-1 inhibition despite aSYN-mediated alterations in mitochondrial morphology and function.


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