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

Journal: The Journal of experimental medicine

Volume: 221

Issue: 5

Year of Publication: 2024

Affiliated Institutions:  Division of Neurodegeneration, Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Translational Neurosciences, Heidelberg University, Mannheim, Germany. Department of Neurology, University of Ulm, Ulm, Germany. Medical Faculty, Munich Cluster for Systems Neurology (SyNergy), Ludwig-Maximilians-University München , Munich, Germany. Neuroproteomics, Max Delbrück Center for Molecular Medicine, Berlin, Germany. Division of Neuroimmunology, Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Translational Neurosciences, Heidelberg University, Mannheim, Germany. Faculty of Medicine, Institute of Biochemistry II, Goethe University Frankfurt, Frankfurt, Germany. Institute of Neuronal Cell Biology, Technical University Munich , Munich, Germany. Electron Microscopy Hub, German Center for Neurodegenerative Diseases, Munich, Germany. Institute of Anatomy and Cell Biology, Ulm University School of Medicine , Ulm, Germany. Institut du Cerveau-Paris Brain Institute-Institut du Cerveau et de la Moelle épinière, Inserm, Centre National de la Recherche Scientifique, Assistance Publique-Hôpitaux de Paris, Hôpital de la Pitié-Salpêtrière, Sorbonne Université , Paris, France. Department of Neurology, Clinical Neuroanatomy Unit, University of Ulm, Ulm, Germany. University of Heidelberg/Medical Faculty Mannheim, Central Institute of Mental Health, Mannheim, Germany.

Abstract summary 

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.

Authors & Co-authors:  Brenner Sieverding Srinidhi Zellner Secker Yilmaz Dyckow Amr Ponomarenko Tunaboylu Douahem Schlag Rodríguez Martínez Kislinger Niemann Nalbach Ruf Uhl Hollenbeck Schirmer Catanese Lobsiger Danzer Yilmazer-Hanke Münch Koch Freischmidt Fetting Behrends Parlato Weishaupt

Study Outcome 

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Citations :  Ahmad, L., Zhang S.-Y., Casanova J.-L., and Sancho-Shimizu V.. 2016. Human TBK1: A gatekeeper of neuroinflammation. Trends Mol. Med. 22:511–527. 10.1016/j.molmed.2016.04.006
Authors :  31
Identifiers
Doi : e20221190
SSN : 1540-9538
Study Population
Male,Female
Mesh Terms
Animals
Other Terms
Study Design
Study Approach
Country of Study
Publication Country
United States