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

A. Iannielli, S. Bido, L. Folladori, A. Segnali, C. Cancellieri, A. Maresca, L. Massimino, A. Rubio, G. Morabito, L. Caporali, F. Tagliavini, O. Musumeci, G. Gregato, E. Bezard, V. Carelli, V. Tiranti, V. Broccoli

Research output: Contribution to journalArticlepeer-review


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)2066-2079
Number of pages14
JournalCell Reports
Issue number8
Publication statusPublished - Feb 2018


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