The necroptosis machinery mediates axonal degeneration in a model of Parkinson disease

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dc.contributor.authorOnate, Maritza
dc.contributor.authorCatenaccio, Alejandra
dc.contributor.authorSalvadores, Natalia
dc.contributor.authorSaquel, Cristian
dc.contributor.authorMartinez, Alexis
dc.contributor.authorMoreno-Gonzalez, Ines
dc.contributor.authorGamez, Nazaret
dc.contributor.authorSoto, Paulina
dc.contributor.authorSoto, Claudio
dc.contributor.authorHetz, Claudio
dc.contributor.authorCourt, Felipe A.
dc.date.accessioned2025-01-23T19:53:02Z
dc.date.available2025-01-23T19:53:02Z
dc.date.issued2020
dc.description.abstractParkinson's disease (PD) is the second most common neurodegenerative condition, characterized by motor impairment due to the progressive degeneration of dopaminergic neurons in the substantia nigra and depletion of dopamine release in the striatum. Accumulating evidence suggest that degeneration of axons is an early event in the disease, involving destruction programs that are independent of the survival of the cell soma. Necroptosis, a programmed cell death process, is emerging as a mediator of neuronal loss in models of neurodegenerative diseases. Here, we demonstrate activation of necroptosis in postmortem brain tissue from PD patients and in a toxin-based mouse model of the disease. Inhibition of key components of the necroptotic pathway resulted in a significant delay of 6-hydroxydopamine-dependent axonal degeneration of dopaminergic and cortical neurons in vitro. Genetic ablation of necroptosis mediators MLKL and RIPK3, as well as pharmacological inhibition of RIPK1 in preclinical models of PD, decreased dopaminergic neuron degeneration, improving motor performance. Together, these findings suggest that axonal degeneration in PD is mediated by the necroptosis machinery, a process here referred to as necroaxoptosis, a druggable pathway to target dopaminergic neuronal loss.
dc.fuente.origenWOS
dc.identifier.doi10.1038/s41418-019-0408-4
dc.identifier.eissn1476-5403
dc.identifier.issn1350-9047
dc.identifier.urihttps://doi.org/10.1038/s41418-019-0408-4
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/100651
dc.identifier.wosidWOS:000520709700002
dc.issue.numero4
dc.language.isoen
dc.pagina.final1185
dc.pagina.inicio1169
dc.revistaCell death and differentiation
dc.rightsacceso restringido
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleThe necroptosis machinery mediates axonal degeneration in a model of Parkinson disease
dc.typeartículo
dc.volumen27
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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