TY  - JOUR
AU  - Brenner, David
AU  - Sieverding, Kirsten
AU  - Srinidhi, Jahnavi
AU  - Zellner, Susanne
AU  - Secker, Christopher
AU  - Yilmaz, Rüstem
AU  - Dyckow, Julia
AU  - Amr, Shady
AU  - Ponomarenko, Anna
AU  - Tunaboylu, Esra
AU  - Douahem, Yasmin
AU  - Schlag, Joana S
AU  - Rodriguez Martinez, Lucia
AU  - Kislinger, Georg
AU  - Niemann, Cornelia
AU  - Nalbach, Karsten
AU  - Ruf, Wolfgang P
AU  - Uhl, Jonathan
AU  - Hollenbeck, Johanna
AU  - Schirmer, Lucas
AU  - Catanese, Alberto
AU  - Lobsiger, Christian S
AU  - Danzer, Karin M
AU  - Yilmazer-Hanke, Deniz
AU  - Münch, Christian
AU  - Koch, Philipp
AU  - Freischmidt, Axel-Dieter
AU  - Fetting, Martina
AU  - Behrends, Christian
AU  - Parlato, Rosanna
AU  - Weishaupt, Jochen H
TI  - A TBK1 variant causes autophagolysosomal and motoneuron pathology without neuroinflammation in mice.
JO  - Journal of experimental medicine
VL  - 221
IS  - 5
SN  - 0022-1007
CY  - New York, NY
PB  - Rockefeller Univ. Press
M1  - DZNE-2024-00305
SP  - e20221190
PY  - 2024
AB  - Heterozygous mutations in the TBK1 gene can cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The majority of TBK1-ALS/FTD patients carry deleterious loss-of-expression mutations, and it is still unclear which TBK1 function leads to neurodegeneration. We investigated the impact of the pathogenic TBK1 missense variant p.E696K, which does not abolish protein expression, but leads to a selective loss of TBK1 binding to the autophagy adaptor protein and TBK1 substrate optineurin. Using organelle-specific proteomics, we found that in a knock-in mouse model and human iPSC-derived motor neurons, the p.E696K mutation causes presymptomatic onset of autophagolysosomal dysfunction in neurons precipitating the accumulation of damaged lysosomes. This is followed by a progressive, age-dependent motor neuron disease. Contrary to the phenotype of mice with full Tbk1 knock-out, RIPK/TNF-α-dependent hepatic, neuronal necroptosis, and overt autoinflammation were not detected. Our in vivo results indicate autophagolysosomal dysfunction as a trigger for neurodegeneration and a promising therapeutic target in TBK1-ALS/FTD.
KW  - Animals
KW  - Humans
KW  - Mice
KW  - Amyotrophic Lateral Sclerosis: pathology
KW  - Frontotemporal Dementia: genetics
KW  - Frontotemporal Dementia: metabolism
KW  - Frontotemporal Dementia: pathology
KW  - Motor Neurons: pathology
KW  - Mutation
KW  - Neuroinflammatory Diseases
KW  - Phosphorylation
KW  - Protein Serine-Threonine Kinases: genetics
KW  - Protein Serine-Threonine Kinases: metabolism
KW  - Protein Serine-Threonine Kinases (NLM Chemicals)
KW  - TBK1 protein, human (NLM Chemicals)
KW  - Tbk1 protein, mouse (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:38517332
C2  - pmc:PMC10959724
DO  - DOI:10.1084/jem.20221190
UR  - https://pub.dzne.de/record/268729
ER  -