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Aging (Albany NY). 2019 Apr 30;11(8):2457-2476. doi: 10.18632/aging.101936.

Deletion of Tbk1 disrupts autophagy and reproduces behavioral and locomotor symptoms of FTD-ALS in mice.

Duan W1,2,3, Guo M1, Yi L1, Zhang J1, Bi Y1, Liu Y1, Li Y1, Li Z1, Ma Y4, Zhang G4, Liu Y1,2,3, Song X1,2,3, Li C1,2,3.

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Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China.
Neurological Laboratory of Hebei Province, Shijiazhuang, People's Republic of China.
Institute of Cardiocerebrovascular Disease, Shijiazhuang, People's Republic of China.
Jiangsu Nhwa Pharmaceutical Co. Ltd, Nantong 226000, People's Republic of China.


Haploinsufficiency of the protein kinase Tbk1 has shown to cause both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD); however, the pathogenic mechanisms are unclear. Here we show that conditional neuronal deletion of Tbk1 in leads to cognitive and locomotor deficits in mice. Tbk1-NKO mice exhibited numerous neuropathological changes, including neurofibrillary tangles, abnormal dendrites, reduced dendritic spine density, and cortical synapse loss. The Purkinje cell layer of the cerebellum presented dendritic swelling, abnormally shaped astrocytes, and p62- and ubiquitin-positive aggregates, suggesting impaired autophagy. Inhibition of autophagic flux with bafilomycin A increased total Tkb1 levels in motor neuron-like cells in vitro, suggesting autophagy-dependent degradation of Tbk1. Although Tbk1 over-expression did not affect mutant SOD1 levels in SOD1G93A-transfected cells, it increased the soluble/insoluble ratio and reduced the number and size of SOD1G93A aggregates. Finally, in vivo experiments showed that Tkb1 expression was reduced in SOD1G93A ALS transgenic mice, which showed decreased p62 protein aggregation and extended survival after ICV injection of adeno-associated viral vectors encoding Tbk1. These data shed light on the neuropathological changes that result from Tbk1 deficiency and hint at impaired autophagy as a contributing factor to the cognitive and locomotor deficits that characterize FTD-ALS in patients with Tkb1 haploinsufficiency.


Tbk1; amyotrophic lateral sclerosis; autophagy; frontotemporal dementia; p62

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