The overexpression of TDP-43 in astrocytes causes neurodegeneration via a PTP1B-mediated inflammatory response
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RESEARCH
Open Access
The overexpression of TDP-43 in astrocytes causes neurodegeneration via a PTP1Bmediated inflammatory response Shinrye Lee1†, Seyeon Kim1,2†, Ha-Young Kang3, Hye Ryeong Lim4, Younghwi Kwon1,2, Myungjin Jo1, Yu-Mi Jeon1, Sang Ryong Kim5,6, Kiyoung Kim7, Chang Man Ha4, Seongsoo Lee3* and Hyung-Jun Kim1*
Abstract Background: Cytoplasmic 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. Methods: To 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. Results: PTP1B 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. Conclusions: These results indicate that PTP1B inhibition mitigates the neuronal toxicity caused by TDP-43-induced inflammation in mammalian astrocytes and Drosophila glial cells. Keywords: Neurodegenerative disease, Neuroinflammation, Astrocytes, Tar DNA-binding protein 43, Protein tyrosine phosphatase 1B
* Correspondence: [email protected]; [email protected] † Shinrye Lee and Seyeon Kim contributed equally to this work. 3 Gwangju Center, Korea Basic Science Institute (KBSI), Gwangju 61886, South Korea 1 Dementia Research Group, Korea Brain Research Institute (KBRI), Daegu 41062, South Korea Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licenc
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