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TBK1 overexpression reduces neuronal loss in the P497S UBQLN2 mouse model of ALS/FTD
Journal article   Open access   Peer reviewed

TBK1 overexpression reduces neuronal loss in the P497S UBQLN2 mouse model of ALS/FTD

Shaoteng Wang, Melanie A. Dolce, Angelina M. Burkett, Victoria L. Collis, Peyton E. Fuller, Grace A. Blanco, Nhat T.T. Le, John H. Fingert and Mervyn J. Monteiro
Neurobiology of disease, Vol.229, 107611
09/19/2026
DOI: 10.1016/j.nbd.2026.107611
PMID: 42763025
url
https://doi.org/10.1016/j.nbd.2026.107611View
Published (Version of record) Open Access

Abstract

Missense mutations in UBQLN2 are linked to dominant inheritance of amyotrophic lateral sclerosis (ALS) which is frequently accompanied by frontotemporal dementia (FTD). The encoded UBQLN2 protein functions to maintain proteostasis, collapse of which is increasingly being realized as the cause of many neurodegenerative diseases. During investigations of our UBQLN2 mouse models of ALS/FTD, we observed a significant decline in Tank-binding kinase 1 (TBK1) protein in end-stage mice. The decline could be significant, as haploinsufficiency of TBK1 expression is linked to ALS/FTD. To determine whether the reduction in TBK1 levels is responsible for driving pathogenesis, we crossed P497S UBQLN2 transgenic (Tg) mice with BacTBK1 Tg mice that overexpress TBK1 and analyzed the progeny for signs of pathology. The analysis revealed that double transgenic mice had a significant reduction in neurodegeneration in both the brain and spinal cord (SC) compared to P497S single-Tg mice. Double immunofluorescence staining of P497S mouse tissue revealed TBK1 colocalizes with UBQLN2 aggregates in spinal motor neurons. Biochemical extraction studies of mouse brain tissue revealed increased enrichment of TBK1 along with wild type and mutant UBQLN2 proteins in detergent-insoluble material, suggesting TBK1 gets sequestered by UBQLN2 aggregates. GST-pulldown assays revealed that UBQLN2 binds directly with TBK1, but paradoxically the P497S mutation was found to reduce TBK1 binding. Turnover studies indicated that loss of UBQLN2 destabilizes TBK1, providing another route for its reduction. These findings lead us to propose that efforts directed toward increasing TBK1 expression may provide a therapeutic approach for treating ALS/FTD caused by UBQLN2 mutations. [Display omitted] •TBK1 levels are reduced in UBQLN2 mouse models of ALS.•Overexpression of TBK1 reduces neuronal loss in the P497S UBQLN2 mouse model of ALS.•Overexpression of TBK1 reduces motor neuron loss in the P497S mouse model of ALS.•TKB1 binds directly with UBQLN2.•Loss of UBQLN2 accelerates TBK1 turnover.
 Amyotrophic Lateral Sclerosis Motor neuron disease Proteostasis TBK1 UBQLN2

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