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A TBK1 variant causes autophagolysosomal and motoneuron pathology without neuroinflammation in mice

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 i...

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Main Authors: Brenner, David (Author) , Sieverding, Kirsten (Author) , Srinidhi, Jahnavi (Author) , Zellner, Susanne (Author) , Secker, Christopher (Author) , Yılmaz, Rüstem (Author) , Dyckow, Julia (Author) , Amr, Shady (Author) , Ponomarenko, Anna (Author) , Tunaboylu, Esra (Author) , Douahem, Yasmin (Author) , Schlag, Joana S. (Author) , Rodríguez Martínez, Lucía (Author) , Kislinger, Georg (Author) , Niemann, Cornelia (Author) , Nalbach, Karsten (Author) , Ruf, Wolfgang P. (Author) , Uhl, Jonathan (Author) , Hollenbeck, Johanna (Author) , Schirmer, Lucas (Author) , Catanese, Alberto (Author) , Lobsiger, Christian S. (Author) , Danzer, Karin M. (Author) , Yilmazer-Hanke, Deniz (Author) , Münch, Christian (Author) , Koch, Philipp (Author) , Freischmidt, Axel (Author) , Fetting, Martina (Author) , Behrends, Christian (Author) , Parlato, Rosanna (Author) , Weishaupt, Jochen H. (Author)
Format: Article (Journal)
Language:English
Published: March 22 2024
In: Journal of experimental medicine
Year: 2024, Volume: 221, Issue: 5, Pages: 1-20
ISSN:1540-9538
DOI:10.1084/jem.20221190
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1084/jem.20221190
Verlag, kostenfrei, Volltext: https://rupress.org/jem/article/221/5/e20221190/276649/A-TBK1-variant-causes-autophagolysosomal-and
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Author Notes:David Brenner, Kirsten Sieverding, Jahnavi Srinidhi, Susanne Zellner, Christopher Secker, Rüstem Yilmaz, Julia Dyckow, Shady Amr, Anna Ponomarenko, Esra Tunaboylu, Yasmin Douahem, Joana S. Schlag, Lucía Rodríguez Martínez, Georg Kislinger, Cornelia Niemann, Karsten Nalbach, Wolfgang P. Ruf, Jonathan Uhl, Johanna Hollenbeck, Lucas Schirmer, Alberto Catanese, Christian S. Lobsiger, Karin M. Danzer, Deniz Yilmazer-Hanke, Christian Münch, Philipp Koch, Axel Freischmidt, Martina Fetting, Christian Behrends, Rosanna Parlato, and Jochen H. Weishaupt

MARC

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520 |a 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. 
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