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

Abstract

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 vivo, 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.

Cobalt nanoparticles trigger ferroptosis‐like cell death (oxytosis) in neuronal cells: Potential implications for neurodegenerative disease

“…Loss of the axonal network is considered a cardinal feature of the early stages of PD . Other authors have presented evidence for a necroptosis‐dependent pathway of axonal degeneration in an animal model of PD . The present study does not refute this suggestion, though we can unequivocally conclude that cell death with loss of axonal integrity is linked to GSH depletion.…”

“…Furthermore, we observed a loss of axonal integrity especially at high doses (50 μg/mL). Loss of the axonal network is considered a cardinal feature of the early stages of PD . Other authors have presented evidence for a necroptosis‐dependent pathway of axonal degeneration in an animal model of PD .…”

Toxicity of Necrostatin-1 in Parkinson’s Disease Models

“…In addition, 6-OHDA induced necroptosis in mesencephalic and cortical neurons. Nevertheless, inhibition through RIP1 or MLKL did not reduce nuclei condensation but did protect against axonal degeneration [ 16 ]. Most certainly, Nec-1 doses beneath 30 μM showed a neuroprotective effect on 6-OHDA-treated PC12 cells [ 17 ].…”

“…The involvement of necroptosis in PD has been demonstrated in animals injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [ 15 ], with 6-OHDA and in postmortem PD midbrain samples [ 16 ] through an increase in MLKL phosphorylation. In addition, necrostatin-1 (Nec-1), an inhibitor of the necroptotic pathway, exerts a neuroprotective effect on 6-OHDA-treated pheochromocytoma (PC12) cells [ 17 ], on MPTP-treated mice [ 15 , 18 ], and prevents neurite degeneration in 6-OHDA mesencephalic neurons [ 16 ]. Although non-apoptotic death induced by MPP + was shown to be inhibited by Nec-1 in differentiated SH-SY5Y cells, this was not classified as necroptosis [ 10 ].…”

Targeting necroptosis in anticancer therapy: mechanisms and modulators

“…Necroptosis could mediate neuronal loss in neurogenerative diseases. Either inhibition of RIPK1 or the knockdown of RIPK3 and MLKL was able to decrease degeneration, suggesting inhibiting necroptosis was favorable in treating neurodegenerative diseases 145 . Overexpression of RIPK3 was observed in human Paneth cells and increased necroptosis in Crohn's disease, suggesting potential therapeutic effect of necroptosis inhibition 146 .…”