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

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2019-10-07

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Oñate, Maritza
Catenaccio, Alejandra
Salvadores, Natalia
Saquel, Cristian
Martinez, Alexis
Moreno-Gonzalez, Ines
Gamez, Nazaret
Soto, Paulina
Soto, Claudio
Hetz, Claudio

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Parkinson'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.

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Animals
Axons
Biomarkers
Disease Models, Animal
Dopaminergic Neurons
Humans
Mice, Inbred C57BL
Mice, Knockout
Motor Activity
Necroptosis
Nerve Degeneration
Neurites
Oxidopamine
Parkinson Disease
Phosphorylation
Protein Kinases
Receptor-Interacting Protein Serine-Threonine Kinases
Substantia Nigra

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