The overexpression of TDP-43 in astrocytes causes neurodegeneration via a PTP1B-mediated inflammatory response

Journal of Neuroinflammation

Myungjin Jo¹  Hyung-Jun Kim¹  Shinrye Lee¹  Yu-Mi Jeon¹  Seyeon Kim²  Younghwi Kwon²  Kiyoung Kim³  Ha-Young Kang⁴  Seongsoo Lee⁴  Hye Ryeong Lim⁵  Chang Man Ha⁵  Sang Ryong Kim⁶ 

[1] Dementia Research Group, Korea Brain Research Institute (KBRI), 41062, Daegu, South Korea;Dementia Research Group, Korea Brain Research Institute (KBRI), 41062, Daegu, South Korea;Department of Brain & Cognitive Sciences, DGIST, 42988, Daegu, South Korea;Department of Medical Biotechnology, Soonchunhyang University, 31538, Asan, South Korea;Gwangju Center, Korea Basic Science Institute (KBSI), 61886, Gwangju, South Korea;Research Division and Brain Research Core Facilities, Korea Brain Research Institute (KBRI), 41062, Daegu, South Korea;School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Institute of Life Science & Biotechnology, Kyungpook National University, 41566, Daegu, South Korea;Brain Science and Engineering Institute, Kyungpook National University, 41944, Daegu, South Korea;

关键词: Neurodegenerative disease;    Neuroinflammation;    Astrocytes;    Tar DNA-binding protein 43;    Protein tyrosine phosphatase 1B;   

DOI  :  10.1186/s12974-020-01963-6

来源: Springer

【 摘 要 】

BackgroundCytoplasmic inclusions of transactive response DNA binding protein of 43 kDa (TDP-43) in neurons and astrocytes are a feature of some neurodegenerative diseases, such as frontotemporal lobar degeneration with TDP-43 (FTLD-TDP) and amyotrophic lateral sclerosis (ALS). However, the role of TDP-43 in astrocyte pathology remains largely unknown.MethodsTo investigate whether TDP-43 overexpression in primary astrocytes could induce inflammation, we transfected primary astrocytes with plasmids encoding Gfp or TDP-43-Gfp. The inflammatory response and upregulation of PTP1B in transfected cells were examined using quantitative RT-PCR and immunoblot analysis. Neurotoxicity was analysed in a transwell coculture system of primary cortical neurons with astrocytes and cultured neurons treated with astrocyte-conditioned medium (ACM). We also examined the lifespan, performed climbing assays and analysed immunohistochemical data in pan-glial TDP-43-expressing flies in the presence or absence of a Ptp61f RNAi transgene.ResultsPTP1B inhibition suppressed TDP-43-induced secretion of inflammatory cytokines (interleukin 1 beta (IL-1β), interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-α)) in primary astrocytes. Using a neuron-astrocyte coculture system and astrocyte-conditioned media treatment, we demonstrated that PTP1B inhibition attenuated neuronal death and mitochondrial dysfunction caused by overexpression of TDP-43 in astrocytes. In addition, neuromuscular junction (NMJ) defects, a shortened lifespan, inflammation and climbing defects caused by pan-glial overexpression of TDP-43 were significantly rescued by downregulation of ptp61f (the Drosophila homologue of PTP1B) in flies.ConclusionsThese results indicate that PTP1B inhibition mitigates the neuronal toxicity caused by TDP-43-induced inflammation in mammalian astrocytes and Drosophila glial cells.

【 授权许可】

CC BY