Deletion of Ripk3 Prevents Motor Neuron Death In Vitro but not In Vivo

ENeuro
Georgia DermentzakiS Przedborski

Abstract

Increasing evidence suggests that necroptosis, a form of programmed cell death (PCD), contributes to neurodegeneration in several disorders, including ALS. Supporting this view, investigations in both in vitro and in vivo models of ALS have implicated key molecular determinants of necroptosis in the death of spinal motor neurons (MNs). Consistent with a pathogenic role of necroptosis in ALS, we showed increased mRNA levels for the three main necroptosis effectors Ripk1, Ripk3, and Mlkl in the spinal cord of mutant superoxide dismutase-1 (SOD1G93A) transgenic mice (Tg), an established model of ALS. In addition, protein levels of receptor-interacting protein kinase 1 (RIPK1; but not of RIPK3, MLKL or activated MLKL) were elevated in spinal cord extracts from these Tg SOD1G93A mice. In postmortem motor cortex samples from sporadic and familial ALS patients, no change in protein levels of RIPK1 were detected. Silencing of Ripk3 in cultured MNs protected them from toxicity associated with SOD1G93A astrocytes. However, constitutive deletion of Ripk3 in Tg SOD1G93A mice failed to provide behavioral or neuropathological improvement, demonstrating no similar benefit of Ripk3 silencing in vivo. Lastly, we detected no genotype-specific my...Continue Reading

Citations

Oct 1, 2020·Cell Death and Differentiation·Sara DominguezBaris Bingol
Nov 21, 2019·Cell Death and Differentiation·Taide WangBradley J Turner
Jan 20, 2021·Cell Death and Differentiation·Yanxiang MengJames M Murphy
Feb 17, 2021·Cell Death and Differentiation·André L SamsonJames M Murphy
Sep 16, 2020·Neuron·Garam KimAaron D Gitler
Apr 16, 2021·Cell Death Discovery·Mathilde Chevin, Guillaume Sébire
May 20, 2021·Trends in Neurosciences·Alexandra C M Van HartenSerge Przedborski
Dec 4, 2021·Cell Death and Differentiation·Taide WangBradley J Turner

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Methods Mentioned

BETA
genotyping
Protein Assay
X-Ray
electron microscopy

Software Mentioned

SigmaPlot
ImageJ

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