Pharmacological Inhibition of Necroptosis Protects from Dopaminergic Neuronal Cell Death in Parkinson's Disease Models

Angelo Iannielli, Simone Bido, Lucrezia Folladori, Alice Segnali, Cinzia Cancellieri, Alessandra Maresca, Luca Massimino, Alicia Rubio, Giuseppe Morabito, Leonardo Caporali, Francesca Tagliavini, Olimpia Musumeci, Giuliana Gregato, Erwan Bezard, Valerio Carelli, Valeria Tiranti, Vania Broccoli

Research output: Contribution to journalArticle

Abstract

Dysfunctions in mitochondrial dynamics and metabolism are common pathological processes associated with Parkinson's disease (PD). It was recently shown that an inherited form of PD and dementia is caused by mutations in the OPA1 gene, which encodes for a key player in mitochondrial fusion and structure. iPSC-derived neural cells from these patients exhibited severe mitochondrial fragmentation, respiration impairment, ATP deficits, and heightened oxidative stress. Reconstitution of normal levels of OPA1 in PD-derived neural cells normalized mitochondria morphology and function. OPA1-mutated neuronal cultures showed reduced survival in vitro. Intriguingly, selective inhibition of necroptosis effectively rescued this survival deficit. Additionally, dampening necroptosis in MPTP-treated mice protected from DA neuronal cell loss. This human iPSC-based model captures both early pathological events in OPA1 mutant neural cells and the beneficial effects of blocking necroptosis, highlighting this cell death process as a potential therapeutic target for PD. Iannielli et al. generate iPSCs from Parkinson's disease patients with OPA1 mutations and find that derived NPCs have mitochondria with impaired morphology and bioenergetics. Nec-1s, a pharmacological inhibitor of necroptosis, promotes the survival of human OPA1 mutant neurons and attenuates dopaminergic neuronal loss in MPTP-treated mice.

Original languageEnglish
Pages (from-to)2094-2106
Number of pages13
JournalCell Reports
Volume22
Issue number8
DOIs
Publication statusPublished - Feb 20 2018

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Keywords

  • apoptosis
  • cell death
  • iPSCs
  • mitochondria
  • necroptosis
  • necrosis
  • neurodegeneration
  • OPA1
  • Parkinson's disease

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Iannielli, A., Bido, S., Folladori, L., Segnali, A., Cancellieri, C., Maresca, A., Massimino, L., Rubio, A., Morabito, G., Caporali, L., Tagliavini, F., Musumeci, O., Gregato, G., Bezard, E., Carelli, V., Tiranti, V., & Broccoli, V. (2018). Pharmacological Inhibition of Necroptosis Protects from Dopaminergic Neuronal Cell Death in Parkinson's Disease Models. Cell Reports, 22(8), 2094-2106. https://doi.org/10.1016/j.celrep.2018.01.089