Genetic inactivation of RIP1 kinase does not ameliorate disease in a mouse model of ALS.
Journal
Cell death and differentiation
ISSN: 1476-5403
Titre abrégé: Cell Death Differ
Pays: England
ID NLM: 9437445
Informations de publication
Date de publication:
03 2021
03 2021
Historique:
received:
29
07
2020
accepted:
11
09
2020
revised:
07
09
2020
pubmed:
1
10
2020
medline:
21
1
2022
entrez:
30
9
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32994544
doi: 10.1038/s41418-020-00625-7
pii: 10.1038/s41418-020-00625-7
pmc: PMC7937687
doi:
Substances chimiques
GTPase-Activating Proteins
0
Ralbp1 protein, mouse
0
Sod1 protein, mouse
EC 1.15.1.1
Superoxide Dismutase-1
EC 1.15.1.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
915-931Références
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