Your browser doesn't support javascript.
loading
A TBK1 variant causes autophagolysosomal and motoneuron pathology without neuroinflammation in mice.
Brenner, David; Sieverding, Kirsten; Srinidhi, Jahnavi; Zellner, Susanne; Secker, Christopher; Yilmaz, Rüstem; Dyckow, Julia; Amr, Shady; Ponomarenko, Anna; Tunaboylu, Esra; Douahem, Yasmin; Schlag, Joana S; Rodríguez Martínez, Lucía; Kislinger, Georg; Niemann, Cornelia; Nalbach, Karsten; Ruf, Wolfgang P; Uhl, Jonathan; Hollenbeck, Johanna; Schirmer, Lucas; Catanese, Alberto; Lobsiger, Christian S; Danzer, Karin M; Yilmazer-Hanke, Deniz; Münch, Christian; Koch, Philipp; Freischmidt, Axel; Fetting, Martina; Behrends, Christian; Parlato, Rosanna; Weishaupt, Jochen H.
Afiliación
  • Brenner D; Division of Neurodegeneration, Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Translational Neurosciences, Heidelberg University, Mannheim, Germany.
  • Sieverding K; Department of Neurology, University of Ulm, Ulm, Germany.
  • Srinidhi J; Department of Neurology, University of Ulm, Ulm, Germany.
  • Zellner S; Division of Neurodegeneration, Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Translational Neurosciences, Heidelberg University, Mannheim, Germany.
  • Secker C; Medical Faculty, Munich Cluster for Systems Neurology (SyNergy), Ludwig-Maximilians-University München , Munich, Germany.
  • Yilmaz R; Neuroproteomics, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
  • Dyckow J; Department of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
  • Amr S; Division of Neurodegeneration, Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Translational Neurosciences, Heidelberg University, Mannheim, Germany.
  • Ponomarenko A; Division of Neuroimmunology, Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Translational Neurosciences, Heidelberg University, Mannheim, Germany.
  • Tunaboylu E; Faculty of Medicine, Institute of Biochemistry II, Goethe University Frankfurt, Frankfurt, Germany.
  • Douahem Y; Department of Neurology, University of Ulm, Ulm, Germany.
  • Schlag JS; Institute of Anatomy and Cell Biology, Ulm University School of Medicine , Ulm, Germany.
  • Rodríguez Martínez L; Department of Neurology, University of Ulm, Ulm, Germany.
  • Kislinger G; Division of Neurodegeneration, Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Translational Neurosciences, Heidelberg University, Mannheim, Germany.
  • Niemann C; Division of Neurodegeneration, Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Translational Neurosciences, Heidelberg University, Mannheim, Germany.
  • Nalbach K; Institute of Neuronal Cell Biology, Technical University Munich , Munich, Germany.
  • Ruf WP; German Center for Neurodegenerative Diseases , Munich, Germany.
  • Uhl J; Electron Microscopy Hub, German Center for Neurodegenerative Diseases, Munich, Germany.
  • Hollenbeck J; Electron Microscopy Hub, German Center for Neurodegenerative Diseases, Munich, Germany.
  • Schirmer L; Medical Faculty, Munich Cluster for Systems Neurology (SyNergy), Ludwig-Maximilians-University München , Munich, Germany.
  • Catanese A; Department of Neurology, University of Ulm, Ulm, Germany.
  • Lobsiger CS; Division of Neurodegeneration, Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Translational Neurosciences, Heidelberg University, Mannheim, Germany.
  • Danzer KM; Division of Neurodegeneration, Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Translational Neurosciences, Heidelberg University, Mannheim, Germany.
  • Yilmazer-Hanke D; Division of Neuroimmunology, Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Translational Neurosciences, Heidelberg University, Mannheim, Germany.
  • Münch C; Institute of Anatomy and Cell Biology, Ulm University School of Medicine , Ulm, Germany.
  • Koch P; 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.
  • Freischmidt A; Department of Neurology, University of Ulm, Ulm, Germany.
  • Fetting M; German Center for Neurodegenerative Diseases , Ulm, Germany.
  • Behrends C; Department of Neurology, Clinical Neuroanatomy Unit, University of Ulm, Ulm, Germany.
  • Parlato R; Institute of Anatomy and Cell Biology, Ulm University School of Medicine , Ulm, Germany.
  • Weishaupt JH; University of Heidelberg/Medical Faculty Mannheim, Central Institute of Mental Health, Mannheim, Germany.
J Exp Med ; 221(5)2024 May 06.
Article en En | MEDLINE | ID: mdl-38517332
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.
Asunto(s)
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Demencia Frontotemporal / Esclerosis Amiotrófica Lateral Límite: Animals / Humans Idioma: En Revista: J Exp Med Año: 2024 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Demencia Frontotemporal / Esclerosis Amiotrófica Lateral Límite: Animals / Humans Idioma: En Revista: J Exp Med Año: 2024 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos