Research Paper Volume 11, Issue 8 pp 2457—2476
Deletion of Tbk1 disrupts autophagy and reproduces behavioral and locomotor symptoms of FTD-ALS in mice
- 1 Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China
- 2 Neurological Laboratory of Hebei Province, Shijiazhuang, People’s Republic of China
- 3 Institute of Cardiocerebrovascular Disease, Shijiazhuang, People’s Republic of China
- 4 Jiangsu Nhwa Pharmaceutical Co. Ltd, Nantong 226000, People’s Republic of China
Received: February 25, 2019 Accepted: April 23, 2019 Published: April 30, 2019https://doi.org/10.18632/aging.101936
How to Cite
Copyright: Duan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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.