TY - JOUR
T1 - Functional and structural consequences of TBK1 missense variants in frontotemporal lobar degeneration and amyotrophic lateral sclerosis
AU - Gurfinkel, Yuval
AU - Polain, Nicole
AU - Sonar, Krushna
AU - Nice, Penelope
AU - Mancera, Ricardo L.
AU - Rea, Sarah Lyn
N1 - Funding Information:
This work was supported by the Dementia Australia Research Foundation and the Racing for MNDi foundation . YG is supported by the Byron Kakulas Prestige Scholarship funded by the Perron Institute for Neurological and Translational Science and an Australian Government Research Training Program Scholarship at The University of Western Australia .
Publisher Copyright:
© 2022
PY - 2022/11
Y1 - 2022/11
N2 - 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.
AB - 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.
KW - Amyotrophic lateral sclerosis
KW - Autophagy
KW - Frontotemporal lobar degeneration
KW - Mitophagy
KW - Neuroinflammation
KW - OPTN: optineurin
KW - SQSTM1: Sequestosome-1/p62
KW - TBK1: TANK-binding kinase 1
UR - http://www.scopus.com/inward/record.url?scp=85138068327&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2022.105859
DO - 10.1016/j.nbd.2022.105859
M3 - Review article
C2 - 36113750
AN - SCOPUS:85138068327
SN - 0969-9961
VL - 174
JO - Neurobiology of Disease
JF - Neurobiology of Disease
M1 - 105859
ER -