Genetic inactivation of RIP1 kinase does not ameliorate disease in a mouse model of ALS
- 29 September 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Differentiation
- Vol. 28 (3), 915-931
- https://doi.org/10.1038/s41418-020-00625-7
Abstract
RIP1 kinase is proposed to play a critical role in driving necroptosis and inflammation in neurodegenerative disorders, including Amyotrophic Lateral Sclerosis (ALS). Preclinical studies indicated that while pharmacological inhibition of RIP1 kinase can ameliorate axonal pathology and delay disease onset in the mutant SOD1 transgenic (SOD1-Tg) mice, genetic blockade of necroptosis does not provide benefit in this mouse model. To clarify the role of RIP1 kinase activity in driving pathology in SOD1-Tg mice, we crossed SOD1-Tgs to RIP1 kinase-dead knock-in mice, and measured disease progression using functional and histopathological endpoints. Genetic inactivation of the RIP1 kinase activity in the SOD1-Tgs did not benefit the declining muscle strength or nerve function, motor neuron degeneration or neuroinflammation. In addition, we did not find evidence of phosphorylated RIP1 accumulation in the spinal cords of ALS patients. On the other hand, genetic inactivation of RIP1 kinase activity ameliorated the depletion of the neurotransmitter dopamine in a toxin model of dopaminergic neurodegeneration. These findings indicate that RIP1 kinase activity is dispensable for disease pathogenesis in the SOD1-Tg mice while inhibition of kinase activity may provide benefit in acute injury models.Keywords
This publication has 68 references indexed in Scilit:
- Automatic Nuclei Segmentation in H&E Stained Breast Cancer Histopathology ImagesPLOS ONE, 2013
- Mlkl knockout mice demonstrate the indispensable role of Mlkl in necroptosisCell Research, 2013
- Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosisNature Neuroscience, 2013
- Mixed Lineage Kinase Domain-like Protein Mediates Necrosis Signaling Downstream of RIP3 KinaseCell, 2012
- Necrostatin-1 ameliorates symptoms in R6/2 transgenic mouse model of Huntington's diseaseCell Death & Disease, 2011
- Mutations of optineurin in amyotrophic lateral sclerosisNature, 2010
- Phosphorylation-Driven Assembly of the RIP1-RIP3 Complex Regulates Programmed Necrosis and Virus-Induced InflammationCell, 2009
- Receptor Interacting Protein Kinase-3 Determines Cellular Necrotic Response to TNF-αCell, 2009
- Pathological TDP‐43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutationsAnnals of Neurology, 2007
- Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosisNature, 1993