2. Academic Validation
  3. Myeloid TBK1 Deficiency Induces Motor Deficits and Axon Degeneration Through Inflammatory Cell Infiltration

Myeloid TBK1 Deficiency Induces Motor Deficits and Axon Degeneration Through Inflammatory Cell Infiltration

  • Mol Neurobiol. 2021 May;58(5):2435-2446. doi: 10.1007/s12035-020-02235-3.
Weisong Duan 1 2 3,  Le Yi 1,  Yunyun Tian 1,  Huai-Peng Huang 4,  Zhongyao Li 1,  Yue Bi 1,  Moran Guo 1,  Yuanyuan Li 1,  Yakun Liu 1,  Yanqin Ma 5,  Xueqin Song 1,  Yaling Liu 1 2 3,  Chunyan Li 6 7 8
Affiliations

Affiliations

  • 1 Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, People's Republic of China.
  • 2 Neurological Laboratory of Hebei Province, Shijiazhuang, Hebei, 050000, People's Republic of China.
  • 3 Institute of Cardiocerebrovascular Disease, Shijiazhuang, Hebei, 050000, People's Republic of China.
  • 4 Shijiazhuang Pingan Hospital, Shijiazhuang, Hebei, 050021, People's Republic of China.
  • 5 Jiangsu Nhwa Pharmaceutical Co. Ltd., Xuzhou, Jiangsu, People's Republic of China.
  • 6 Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, People's Republic of China. hebeichunyanli@aliyun.com.
  • 7 Neurological Laboratory of Hebei Province, Shijiazhuang, Hebei, 050000, People's Republic of China. hebeichunyanli@aliyun.com.
  • 8 Institute of Cardiocerebrovascular Disease, Shijiazhuang, Hebei, 050000, People's Republic of China. hebeichunyanli@aliyun.com.
PMID: 33439438 DOI: 10.1007/s12035-020-02235-3
Abstract

Background: TANK-binding kinase1 (TBK1) haploinsufficiency has been shown to cause both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD); however, the mechanism is unclear.

Methods: Myeloid TBK1 knockout mice (Tbk1-LKO mice) were established and motor function and pathological analyses were also performed. The level of p-TBK1 was analyzed in the ALS animal model and in patient samples using flow cytometry. The expression of inflammatory proteins and mRNAs was analyzed via western blotting and RT-PCR, respectively.

Results: The latency to fall in seven-month-old Tbk1-LKO mice was significantly reduced in evaluations conducted on two consecutive days. Overall, 25.6% of Tbk1-LKO mice presented paralysis symptoms and signs, along with a loosened myelin sheath and axon degeneration at 14-16 months of age. Furthermore, the TBK1 deficiency in myeloid cells induced inflammatory cell infiltration and dysbacteriosis in the digestive tract. Additionally, p-TBK1 levels were reduced by 29.5% and 14.8% in monocytes of patients with definite ALS and probable ALS and decreased by 27.6% and 45.5% in monocytes and microglia of ALS Animals, respectively. The use of PEI-mannose-TBK1 or PEI-mannose-SaCas9-sgRNA to delete mutant SOD1 in macrophages significantly delayed disease onset and prolonged survival in the mouse model of ALS.

Conclusions: Based on these data, inflammatory monocyte and macrophage infiltration and impaired innate immune defenses contribute to ALS and FTD.

Keywords

Amyotrophic lateral sclerosis; Frontotemporal dementia; Macrophage; Tbk1.

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