Pharmacological Inhibition of Necroptosis Protects from Dopaminergic Neuronal Cell Death in Parkinson’s Disease Models.
Cell Reports. 2018-02-01; 22(8): 2066-2079
DOI: 10.1016/j.celrep.2018.01.089
Lire sur PubMed
1. Cell Rep. 2018 Feb 20;22(8):2066-2079. doi: 10.1016/j.celrep.2018.01.089.
Pharmacological Inhibition of Necroptosis Protects from Dopaminergic Neuronal
Cell Death in Parkinson’s Disease Models.
Iannielli A(1), Bido S(1), Folladori L(1), Segnali A(2), Cancellieri C(1),
Maresca A(3), Massimino L(4), Rubio A(5), Morabito G(6), Caporali L(3),
Tagliavini F(3), Musumeci O(7), Gregato G(8), Bezard E(9), Carelli V(10), Tiranti
V(2), Broccoli V(11).
Author information:
(1)Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan,
Italy.
(2)Molecular Neurogenetics Unit, IRCCS Foundation C. Besta Neurological
Institute, 20126 Milan, Italy.
(3)IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital,
Bologna, Italy.
(4)University of Milano-Bicocca, Department of Medicine and Surgery, Monza,
Italy.
(5)Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan,
Italy; National Research Council (CNR), Institute of Neuroscience, 20129 Milan,
Italy.
(6)Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan,
Italy; University of Milano-Bicocca, Milan, Italy.
(7)Department of Neuroscience, University of Messina, Messina, Italy.
(8)Division of Clinical Haematology-Oncology, European Institute of Oncology,
Milan, Italy.
(9)Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293,
F-33000 Bordeaux, France.
(10)IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital,
Bologna, Italy; Neurology Unit, Department of Biomedical and Neuromotor Sciences,
University of Bologna, Bologna, Italy.
(11)Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan,
Italy; National Research Council (CNR), Institute of Neuroscience, 20129 Milan,
Italy. Electronic address: .
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.
Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.celrep.2018.01.089
PMCID: PMC5842028
PMID: 29466734