Necroptosis is dispensable for motor neuron degeneration in a mouse model of ALS
Details
Publication Year 2019-05, Volume 27, Issue #5, Page 1728-1739
Journal Title
Cell Death and Differentiation
Publication Type
Journal Article
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 (SOD1(G93A)) 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 SOD1(G93A) mice. Disease onset, progression, and survival were not affected in SOD1(G93A) mice lacking MLKL. Motor neuron degeneration and activation of neuroinflammatory cells, astrocytes, and microglia, were independent of MLKL expression in SOD1(G93A) mice. While RIPK1 accumulation occurred in spinal cords of SOD1(G93A) mice in late stage disease, RIPK3 and MLKL expression levels were not detected in central nervous system tissues from normal or SOD1(G93A) 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.
Publisher
NPG
WEHI Research Division(s)
Inflammation
PubMed ID
31745214
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2019-12-05 01:26:22
Last Modified: 2021-05-12 10:28:13
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