Deleting TBK1 Entirely Slows Disease Progression in ALS Model Mice

Complete deletion of the gene TBK1 attenuates microglial activation and slows disease progression in a mouse model of amyotrophic lateral sclerosis, according to a new study published in Acta Neuropathologica Communications. The finding is notable because total loss of TBK1 was long thought impossible to study in living animals: mice lacking both copies of the gene die during embryonic development, leaving researchers to rely on partial deletions whose effects proved difficult to interpret.

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by the selective degeneration of motor neurons and by neuroinflammation, the immune-driven inflammation within the nervous system. Heterozygous loss-of-function variants in the TBK1 gene, meaning variants that disable one of the two copies carried by each person, are sufficient to cause ALS in patients. This pattern indicates that TBK1 haploinsufficiency, having too little of the protein rather than none at all, is itself a disease mechanism.

TBK1 encodes a serine/threonine kinase involved in multiple cellular pathways, including autophagy, the cellular recycling process, and innate immune signaling, the body’s first-line defense machinery. Because the protein sits at the intersection of these processes, its contribution to neuroinflammation in ALS has remained unclear. Earlier work in ALS model mice showed that global heterozygous or motor neuron-specific Tbk1 deletion accelerates disease onset but then slows disease progression and suppresses neuroinflammation, with global heterozygous deletion also extending survival. In contrast, deleting Tbk1 only in microglia, the resident immune cells of the brain and spinal cord, does not alter the disease course at all.

To overcome the embryonic lethality of complete TBK1 loss, the research team, led by Mai Horiuchi, Seiji Watanabe, Okiru Komine and Koji Yamanaka among colleagues, established Tbk1/Tnf double-knockout mice. By simultaneously removing Tnf, a gene whose product drives inflammatory signaling, the animals survive to birth, allowing the researchers to investigate the effects of complete TBK1 deletion in two distinct neuroinflammation models.

In the SOD1-G93A chronic ALS model, a widely used mouse line carrying a human mutant SOD1 gene, complete Tbk1 deletion accelerated disease onset but significantly extended disease duration without altering overall lifespan. The animals showed suppressed microgliosis, a reduction in the activation and proliferation of microglia, both at disease onset and at end-stage. The dissociation between disease duration and survival is striking: the mice lived no longer, but they spent more of their lives in a slower-progressing disease state.

To understand the mechanism, the researchers performed RNA sequencing on spinal cord microglia. The analysis revealed upregulation of homeostatic microglial genes, the molecular program that defines microglia in their normal, resting state, and downregulation of marker genes for disease-associated microglia, known as DAM, and for interferon-responsive microglia, known as IRM. These two populations represent inflammatory states that microglia adopt in diseased nervous tissue. The pattern suggests that reduced type I interferon signaling, a key antiviral and inflammatory pathway controlled by TBK1, underlies the attenuated microglial activation observed in the knockout animals.

The effect, however, proved context-dependent. In a sciatic nerve axotomy model, an acute injury paradigm in which a peripheral nerve is cut to trigger a rapid inflammatory response, Tbk1 deletion did not affect neuroinflammation at all. Instead, the researchers identified Tnf deletion as the primary driver of microglial suppression in that setting. The contrast indicates that TBK1-mediated interferon signaling is specifically relevant to chronic neuroinflammation rather than to acute injury responses.

The study also carries a caution about therapeutic translation. The dissociation between extended disease duration and unchanged lifespan in mice with complete TBK1 deficiency contrasts with the survival extension previously reported in ALS mice with heterozygous TBK1 deficiency. The authors note that the relationship between the degree of TBK1 loss and its net effect on ALS pathology is not simply linear, meaning that complete and partial inhibition of the pathway can produce opposing outcomes.

Nevertheless, the researchers report that their findings demonstrate for the first time that complete Tbk1 deletion attenuates chronic microglial activation and slows disease progression in SOD1-ALS mice. They establish TBK1-mediated interferon signaling as a therapeutic target in ALS, while emphasizing that, given the potential for opposing effects of complete versus partial TBK1 inhibition, any future strategy will need to be pathway-selective to maximize benefit. The work was published as an open-access article on 27 October 2026.

Subject of Research: The role of complete TBK1 deletion in microglial activation and disease progression in an ALS mouse model

Article Title: Complete TBK1 deletion attenuates microglial activation and slows disease progression in SOD1-ALS model mice

Article References: Horiuchi, M., Watanabe, S., Komine, O., Shimada, M., Konishi, H., Ogi, T., & Yamanaka, K. (2026). Complete TBK1 deletion attenuates microglial activation and slows disease progression in SOD1-ALS model mice. Acta Neuropathologica Communications. https://doi.org/10.1186/s40478-026-02474-w

Image Credits: AI Generated

DOI: 10.1186/s40478-026-02474-w

Keywords: ALS, TBK1, microglia, neuroinflammation, SOD1-G93A, interferon signaling, type I interferon, disease-associated microglia, autophagy, innate immunity, motor neuron disease, Tbk1/Tnf double-knockout