Functional and structural consequences of TBK1 missense variants in frontotemporal lobar degeneration and amyotrophic lateral sclerosis
Mutations in the Tank-binding kinase 1 (TBK1) gene were identified in 2015 in individuals with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). They account for ∼3–4% of cases. To date, over 100 distinct mutations, including missense, nonsense, deletion, insertion, d...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-11-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996122002510 |
| _version_ | 1811329317169266688 |
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| author | Yuval Gurfinkel Nicole Polain Krushna Sonar Penelope Nice Ricardo L. Mancera Sarah Lyn Rea |
| author_facet | Yuval Gurfinkel Nicole Polain Krushna Sonar Penelope Nice Ricardo L. Mancera Sarah Lyn Rea |
| author_sort | Yuval Gurfinkel |
| collection | DOAJ |
| description | Mutations in the Tank-binding kinase 1 (TBK1) gene were identified in 2015 in individuals with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). They account for ∼3–4% of cases. To date, over 100 distinct mutations, including missense, nonsense, deletion, insertion, duplication, and splice-site mutations have been reported. While nonsense mutations are predicted to cause disease via haploinsufficiency, the mechanisms underlying disease pathogenesis with missense mutations is not fully elucidated. TBK1 is a kinase involved in neuroinflammation, which is commonly observed in these diseases. TBK1 also phosphorylates key autophagy mediators, thereby regulating proteostasis, a pathway that is dysregulated in ALS-FTLD. Recently, several groups have characterised various missense mutations with respect to their effects on the phosphorylation of known TBK1 substrates, TBK1 homodimerization, interaction with optineurin, and the regulation of autophagy and neuroinflammatory pathways. Further, the effects of either global or conditional heterozygous knock-out of Tbk1, or the heterozygous or homozygous knock-in of ALS-FTLD associated mutations, alone or when crossed with the SOD1G93A classical ALS mouse model or a TDP-43 mouse model, have been reported. In this review we summarise the known functional effects of TBK1 missense mutations. We also present novel modelling data that predicts the structural effects of missense mutations and discuss how they correlate with the known functional effects of these mutations. |
| first_indexed | 2024-04-13T15:41:40Z |
| format | Article |
| id | doaj.art-224b6571ec0e4e29976a4da442979b09 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-04-13T15:41:40Z |
| publishDate | 2022-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-224b6571ec0e4e29976a4da442979b092022-12-22T02:41:08ZengElsevierNeurobiology of Disease1095-953X2022-11-01174105859Functional and structural consequences of TBK1 missense variants in frontotemporal lobar degeneration and amyotrophic lateral sclerosisYuval Gurfinkel0Nicole Polain1Krushna Sonar2Penelope Nice3Ricardo L. Mancera4Sarah Lyn Rea5Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Health Research Building, Discovery Way, Murdoch, Western Australia, Australia; Perron Institute for Neurological and Translational Science, Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Ralph and Patricia Sarich Neuroscience Building, QEII Medical Centre, Ground floor RR Block, 8 Verdun St, Nedlands, Western Australia 6009, Australia.; UWA Medical School, University of Western Australia, 35 Stirling Highway, Crawley, Western Australia 6009, AustraliaCentre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Health Research Building, Discovery Way, Murdoch, Western Australia, AustraliaCurtin Medical School, Curtin Health Innovation Research Institute, Curtin Institute for Computation, Curtin University, GPO Box U1987, Perth, Western Australia 6845, AustraliaCentre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Health Research Building, Discovery Way, Murdoch, Western Australia, Australia; Perron Institute for Neurological and Translational Science, Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Ralph and Patricia Sarich Neuroscience Building, QEII Medical Centre, Ground floor RR Block, 8 Verdun St, Nedlands, Western Australia 6009, Australia.Curtin Medical School, Curtin Health Innovation Research Institute, Curtin Institute for Computation, Curtin University, GPO Box U1987, Perth, Western Australia 6845, AustraliaCentre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Health Research Building, Discovery Way, Murdoch, Western Australia, Australia; Perron Institute for Neurological and Translational Science, Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Ralph and Patricia Sarich Neuroscience Building, QEII Medical Centre, Ground floor RR Block, 8 Verdun St, Nedlands, Western Australia 6009, Australia.; Corresponding author at: Building 390, Discovery drive, Murdoch, Western Australia 6150, Australia.Mutations in the Tank-binding kinase 1 (TBK1) gene were identified in 2015 in individuals with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). They account for ∼3–4% of cases. To date, over 100 distinct mutations, including missense, nonsense, deletion, insertion, duplication, and splice-site mutations have been reported. While nonsense mutations are predicted to cause disease via haploinsufficiency, the mechanisms underlying disease pathogenesis with missense mutations is not fully elucidated. TBK1 is a kinase involved in neuroinflammation, which is commonly observed in these diseases. TBK1 also phosphorylates key autophagy mediators, thereby regulating proteostasis, a pathway that is dysregulated in ALS-FTLD. Recently, several groups have characterised various missense mutations with respect to their effects on the phosphorylation of known TBK1 substrates, TBK1 homodimerization, interaction with optineurin, and the regulation of autophagy and neuroinflammatory pathways. Further, the effects of either global or conditional heterozygous knock-out of Tbk1, or the heterozygous or homozygous knock-in of ALS-FTLD associated mutations, alone or when crossed with the SOD1G93A classical ALS mouse model or a TDP-43 mouse model, have been reported. In this review we summarise the known functional effects of TBK1 missense mutations. We also present novel modelling data that predicts the structural effects of missense mutations and discuss how they correlate with the known functional effects of these mutations.http://www.sciencedirect.com/science/article/pii/S0969996122002510Frontotemporal lobar degenerationAmyotrophic lateral sclerosisTBK1: TANK-binding kinase 1SQSTM1: Sequestosome-1/p62OPTN: optineurinAutophagy |
| spellingShingle | Yuval Gurfinkel Nicole Polain Krushna Sonar Penelope Nice Ricardo L. Mancera Sarah Lyn Rea Functional and structural consequences of TBK1 missense variants in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Neurobiology of Disease Frontotemporal lobar degeneration Amyotrophic lateral sclerosis TBK1: TANK-binding kinase 1 SQSTM1: Sequestosome-1/p62 OPTN: optineurin Autophagy |
| title | Functional and structural consequences of TBK1 missense variants in frontotemporal lobar degeneration and amyotrophic lateral sclerosis |
| title_full | Functional and structural consequences of TBK1 missense variants in frontotemporal lobar degeneration and amyotrophic lateral sclerosis |
| title_fullStr | Functional and structural consequences of TBK1 missense variants in frontotemporal lobar degeneration and amyotrophic lateral sclerosis |
| title_full_unstemmed | Functional and structural consequences of TBK1 missense variants in frontotemporal lobar degeneration and amyotrophic lateral sclerosis |
| title_short | Functional and structural consequences of TBK1 missense variants in frontotemporal lobar degeneration and amyotrophic lateral sclerosis |
| title_sort | functional and structural consequences of tbk1 missense variants in frontotemporal lobar degeneration and amyotrophic lateral sclerosis |
| topic | Frontotemporal lobar degeneration Amyotrophic lateral sclerosis TBK1: TANK-binding kinase 1 SQSTM1: Sequestosome-1/p62 OPTN: optineurin Autophagy |
| url | http://www.sciencedirect.com/science/article/pii/S0969996122002510 |
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