The Loss of TBK1 Kinase Activity in Motor Neurons or in All Cell Types Differentially Impacts ALS Disease Progression in SOD1 Mice

• Published in: Neuron (Cambridge, Mass.) Vol. 106; no. 5; pp. 789 - 805.e5
• Main Authors: Gerbino, Valeria, Kaunga, Esther, Ye, Junqiang, Canzio, Daniele, O’Keeffe, Sean, Rudnick, Noam D., Guarnieri, Paolo, Lutz, Cathleen M., Maniatis, Tom
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.06.2020; Elsevier Limited
• Subjects: ALS; Amyotrophic Lateral Sclerosis; Autophagy; glia; Interferon; interferon response; Kinases; Life span; motor neuron autophagy; Motor neurons; Mutation; Neurodegeneration; Neurodegenerative diseases; neuroinflammation; Neuronal-glial interactions; Nucleotide sequence; Phagocytosis; Phenotypes; Rodents; selective autophagy; SOD1 mouse model; Spinal cord; Superoxide dismutase; TBK1; motor neuron autophagy; Amyotrophic Lateral Sclerosis; TBK1; neuroinflammation; selective autophagy; ALS; SOD1 mouse model; glia; interferon response
• ISSN: 0896-6273; 1097-4199; 1097-4199
• DOI: 10.1016/j.neuron.2020.03.005

DNA sequence variants in the TBK1 gene associate with or cause sporadic or familial amyotrophic lateral sclerosis (ALS). Here we show that mice bearing human ALS-associated TBK1 missense loss-of-function mutations, or mice in which the Tbk1 gene is selectively deleted in motor neurons, do not display a neurodegenerative disease phenotype. However, loss of TBK1 function in motor neurons of the SOD1G93A mouse model of ALS impairs autophagy, increases SOD1 aggregation, and accelerates early disease onset without affecting lifespan. By contrast, point mutations that decrease TBK1 kinase activity in all cells also accelerate disease onset but extend the lifespan of SOD1 mice. This difference correlates with the failure to activate high levels of expression of interferon-inducible genes in glia. We conclude that loss of TBK1 kinase activity impacts ALS disease progression through distinct pathways in different spinal cord cell types and further implicate the importance of glia in neurodegeneration. [Display omitted] •TBK1 kinase activity regulates disease progression in an ALS SOD1 mouse model•Loss of TBK1 in motor neurons increases SOD1 aggregation and accelerates disease onset•Loss of TBK1 activity in all cell types accelerates disease onset but extends survival•Loss of TBK1 activity in all cell types reduces the IFN response in microglia DNA sequence variants in the TBK1 gene associate with familial and sporadic ALS. Gerbino et al. show that partial or complete loss-of-function TBK1 mutations alone do not induce neurodegeneration in mice. However, they profoundly affect disease onset and progression in the SOD1 ALS mouse model.