Abstract
Motor neuron degeneration in amyotrophic lateral sclerosis (ALS) is proposed to occur by necroptosis, an inflammatory form of regulated cell death. Prior studies implicated necroptosis in ALS based on accumulation of necroptotic markers in affected tissues of patients and mouse models, and amelioration of disease in mutant superoxide dismutase 1 (SOD1G93A) mice with inhibition of the upstream necroptotic mediators, receptor interacting protein kinase 1 (RIPK1), and RIPK3. To definitively address the pathogenic role of necroptosis in ALS, we genetically ablated the critical terminal executioner of necroptosis, mixed lineage kinase domain-like protein (MLKL), in SOD1G93A mice. Disease onset, progression, and survival were not affected in SOD1G93A mice lacking MLKL. Motor neuron degeneration and activation of neuroinflammatory cells, astrocytes, and microglia, were independent of MLKL expression in SOD1G93A mice. While RIPK1 accumulation occurred in spinal cords of SOD1G93A mice in late stage disease, RIPK3 and MLKL expression levels were not detected in central nervous system tissues from normal or SOD1G93A mice at any disease stage. These findings demonstrate that necroptosis does not play an important role in motor neuron death in ALS, which may limit the potential of therapeutic targeting of necroptosis in the treatment of neurological disorders.
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Funding
Funding for this project was provided by the Australian NHMRC (Project Grants 1104295, 1104299 and Fellowship 1137024 to BJT; Project Grants 1124735, 1124737, Fellowship 1105754 and IRIISS 9000433 to JMM), SciOpen Research Group and Stafford Fox Medical Research Foundation. TW was supported by the Angie Cunningham FightMND PhD Scholarship and Grant. NDP was supported by a Motor Neurone Disease Research Institute Australia MND Postdoctoral Fellowship. WC was supported by the CareerTrackers Indigenous Internship Program at the Walter & Eliza Hall Institute of Medical Research. The Florey Institute of Neuroscience & Mental Health and Walter & Eliza Hall Institute acknowledge Victorian Government Operational Infrastructure Support.
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JMM contributes to a program developing inhibitors of necroptosis with Anaxis Pharma Pty Ltd. The other authors declare that they have no conflict of interest.
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Wang, T., Perera, N.D., Chiam, M.D.F. et al. Necroptosis is dispensable for motor neuron degeneration in a mouse model of ALS. Cell Death Differ 27, 1728–1739 (2020). https://doi.org/10.1038/s41418-019-0457-8
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DOI: https://doi.org/10.1038/s41418-019-0457-8
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