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

Weisong Duan,Yakun Liu,Yanqin Ma,Guisen Zhang,Chunyan Li,Le Yi,Xueqing Song,Moran Guo,Jie Zhang,Zhongyao Li,Yuanyuan Li,Yaling Liu,Yue Bi

doi:10.18632/aging.101936

Abstract

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.

Highlights

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons in the cortex, brain stem, and spinal cord, behavioral and cognitive symptoms often coexist with amyotrophic lateral sclerosis (ALS) [1,2]
TANK-binding kinase1 (Tbk1) expression was normal in the liver, but barely detectable in the cortex and cerebellum of Tbk1-NKO mice (Figure 1B)
When the experiment was repeated in older mice (14 months), no significant decline in the time to reach the platform was observed over 5 days of training in Tbk1-NKO mice

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons in the cortex, brain stem, and spinal cord, behavioral and cognitive symptoms often coexist with ALS [1,2]. FTD comprises a group of early-onset neurodegenerative syndromes that represent the most common form of dementia in people under age 60 [4,5,6]. Clinical signs and symptoms of ALS and FTD often overlap, implying a common etiology. About ~15% of FTP patients develop motor neuron deficits that are clinically consistent with ALS; between 10%-30% of ALS patients show signs of FTD [7,8].

Methods

Results

Conclusion