This report includes information relevant to a potential model of frontotemporal dementia and/or amyotrophic lateral sclerosis 4 (FTDALS4), which is a subtype of amyotrophic lateral sclerosis. The human gene implicated in this disease is TBK1, which encodes the serine/threonine kinase TANK-binding kinase 1. There is one high-scoring fly ortholog, IKKε, for which RNAi targeting constructs, alleles caused by insertional mutagenesis, and classical amorphic alleles have been generated. TBK1 is also one of four genes, and the most likely candidate, in the genomic region associated with adult-onset open angle glaucoma-1P (GLC1P) (MIM:177700).
A UAS construct for the human Hsap\TBK1 gene has been introduced into flies, but has not been characterized in the context of this disease model.
[updated Jun. 2019 by FlyBase; FBrf0222196]
Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. ALS usually begins with asymmetric involvement of the muscles in middle adult life. Approximately 10% of ALS cases are familial (Siddique and Deng, 1996, pubmed:8875253). ALS is sometimes referred to as 'Lou Gehrig disease' after the famous American baseball player who was diagnosed with the disorder. [from MIM:105400, 2015.02.11]
[FRONTOTEMPORAL DEMENTIA AND/OR AMYOTROPHIC LATERAL SCLEROSIS 4; FTDALS4](https://omim.org/entry/616439)
[TANK-BINDING KINASE 1; TBK1](https://omim.org/entry/604834)
Frontotemporal dementia and/or amyotrophic lateral sclerosis 4 is an autosomal dominant neurodegenerative disorder characterized by adult or late adult onset of cognitive impairment, behavioral abnormalities, and speech apraxia and/or upper and lower motor neuron signs. The phenotype is highly variable (summary by Freischmidt et al., 2015, pubmed:25803835). [From MIM:607641, 2016.01.08]
Frontotemporal dementia and/or amyotrophic lateral sclerosis-4 (FTDALS4) is caused by heterozygous mutation in the TBK1 gene, which encodes TANK-binding kinase 1. [From MIM:616439, 2016.01.21]
TBK1 protein localization is detected in ganglion cells, the retinal nerve fiber layer, and the microvasculature, indicating that TBK1 protein is present in tissues affected by glaucoma (Fingert et al., 2011, pubmed:21447600). [From MIM:604834, 2016.01.22]
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TBK1 is a serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents. Following activation of toll-like receptors by viral or bacterial components, TBK1 associates with TRAF3 and TANK and phosphorylates interferon regulatory factors (IRFs) IRF3 and IRF7 as well as DDX3X. This activity allows subsequent homodimerization and nuclear translocation of the IRFs leading to transcriptional activation of pro-inflammatory and antiviral genes including IFNA and IFNB. In order to establish such an antiviral state, TBK1 forms several different complexes whose composition depends on the type of cell and cellular stimuli. Thus, several scaffolding molecules including FADD, TRADD, MAVS, AZI2, TANK or TBKBP1/SINTBAD can be recruited to the TBK1-containing-complexes. Under particular conditions, TBK1 functions as a NF-kappa-B effector by phosphorylating NF-kappa-B inhibitor alpha/NFKBIA, IKBKB or RELA to translocate NF-Kappa-B to the nucleus. TBK1 estricts bacterial proliferation by phosphorylating the autophagy receptor OPTN/Optineurin on 'Ser-177', thus enhancing LC3 binding affinity and antibacterial autophagy. TBK1 phosphorylates and activates AKT1. It seems to play a role in energy balance regulation by sustaining a state of chronic, low-grade inflammation in obesity, which leads to a negative impact on insulin sensitivity. TBK1 attenuates retroviral budding by phosphorylating the endosomal sorting complex required for transport-I (ESCRT-I) subunit VPS37C. TBK1 phosphorylates Borna disease virus (BDV) P protein. [From UniProt, uniprot:Q9UHD2 2016.01.22]
Many to one: 2 human to 1 Drosophila; the human genes are TBK1 and IKBKE.
Many to one: 2 human to 1 Drosophila; the human genes are TBK1 and IKBKE.
