A perturbed network in neurodegeneration
| Autor: | Jean-Marc Gallo, Dieter Edbauer |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Neurons
TARDBP protein human Multidisciplinary C9orf72 Protein metabolism [Amyotrophic Lateral Sclerosis] Amyotrophic Lateral Sclerosis genetics [DNA-Binding Proteins] genetics [Protein Serine-Threonine Kinases] Protein Serine-Threonine Kinases Article DNA-Binding Proteins genetics [Amyotrophic Lateral Sclerosis] Mice metabolism [Protein Serine-Threonine Kinases] metabolism [C9orf72 Protein] metabolism [Neurons] Frontotemporal Dementia ddc:320 metabolism [Frontotemporal Dementia] Animals Humans metabolism [DNA-Binding Proteins] genetics [C9orf72 Protein] genetics [Frontotemporal Dementia] Tbk1 protein mouse |
| Zdroj: | Science / Science now 378(6615), 28-29 (2022). doi:10.1126/science.ade4210 Science |
| DOI: | 10.1126/science.ade4210 |
| Popis: | Frontotemporal dementia and amyotrophic lateral sclerosis (FTD-ALS) are associated with both a repeat expansion in the C9orf72 gene and mutations in the TANK-binding kinase 1 (TBK1) gene. We found that TBK1 is phosphorylated in response to C9orf72 poly(Gly-Ala) [poly(GA)] aggregation and sequestered into inclusions, which leads to a loss of TBK1 activity and contributes to neurodegeneration. When we reduced TBK1 activity using a TBK1-R228H (Arg(228)→His) mutation in mice, poly(GA)-induced phenotypes were exacerbated. These phenotypes included an increase in TAR DNA binding protein 43 (TDP-43) pathology and the accumulation of defective endosomes in poly(GA)-positive neurons. Inhibiting the endosomal pathway induced TDP-43 aggregation, which highlights the importance of this pathway and TBK1 activity in pathogenesis. This interplay between C9orf72, TBK1, and TDP-43 connects three different facets of FTD-ALS into one coherent pathway. |
| Databáze: | OpenAIRE |
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