Journal Article

DZNE-2024-00305

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png A TBK1 variant causes autophagolysosomal and motoneuron pathology without neuroinflammation in mice.

Brenner, D.Extern* ; Sieverding, K. ; Srinidhi, J. ; Zellner, S. ; Secker, C. ; Yilmaz, R. ; Dyckow, J. ; Amr, S. ; Ponomarenko, A. ; Tunaboylu, E. ; Douahem, Y. ; Schlag, J. S. ; Rodriguez Martinez, L.DZNE* ; Kislinger, G.DZNE* ; Niemann, C.DZNE* ; Nalbach, K.Extern* ; Ruf, W. P.Extern* ; Uhl, J. ; Hollenbeck, J. ; Schirmer, L. ; Catanese, A.Extern* ; Lobsiger, C. S. ; Danzer, K. M.DZNE* ; Yilmazer-Hanke, D. ; Münch, C. ; Koch, P.Extern* ; Freischmidt, A.-D. ; Fetting, M.DZNE* ; Behrends, C. ; Parlato, R. ; Weishaupt, J. H.

2024
Rockefeller Univ. Press New York, NY

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Please use a persistent id in citations: doi:10.1084/jem.20221190

Abstract: 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.

Keyword(s): Animals (MeSH) ; Humans (MeSH) ; Mice (MeSH) ; Amyotrophic Lateral Sclerosis: pathology (MeSH) ; Frontotemporal Dementia: genetics (MeSH) ; Frontotemporal Dementia: metabolism (MeSH) ; Frontotemporal Dementia: pathology (MeSH) ; Motor Neurons: pathology (MeSH) ; Mutation (MeSH) ; Neuroinflammatory Diseases (MeSH) ; Phosphorylation (MeSH) ; Protein Serine-Threonine Kinases: genetics (MeSH) ; Protein Serine-Threonine Kinases: metabolism (MeSH) ; Protein Serine-Threonine Kinases ; TBK1 protein, human ; Tbk1 protein, mouse

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Contributing Institute(s):

1. Molecular Neurobiology (AG Simons)
2. Neuronal Cell Biology (AG Misgeld)
3. Mechanisms of Propagation (AG Danzer)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)
2. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2024

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Essential Science Indicators ; IF >= 15 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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