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

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.

• Authors: Shinrye Lee, Seyeon Kim, Ha-Young Kang, Hye Ryeong Lim, Younghwi Kwon, Myungjin Jo, Yu-Mi Jeon, Sang Ryong Kim, Kiyoung Kim, Chang Man Ha, Seongsoo Lee, Hyung-Jun Kim
• Journal: Journal of neuroinflammation (J Neuroinflammation) Vol. 17 Issue 1 Pg. 299 (Oct 14 2020) ISSN: 1742-2094 [Electronic] England
• PMID: 33054766 (Publication Type: Journal Article)

Chemical References

• DNA-Binding Proteins
• Inflammation Mediators
• TDP-43 protein, mouse
• Protein Tyrosine Phosphatase, Non-Receptor Type 1
• Ptpn1 protein, mouse

Topics

• Animals
• Animals, Genetically Modified
• Astrocytes (metabolism, pathology)
• Cells, Cultured
• DNA-Binding Proteins (biosynthesis, genetics)
• Drosophila
• Gene Expression
• Inflammation Mediators (antagonists & inhibitors, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Nerve Degeneration (genetics, metabolism, pathology)
• Protein Tyrosine Phosphatase, Non-Receptor Type 1 (antagonists & inhibitors, biosynthesis, genetics)