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Identification of Genetic Modifiers of TDP-43: Inflammatory Activation of Astrocytes for Neuroinflammation.

Authors
  • Kim, Jae-Hong1, 2
  • Rahman, Md Habibur1, 2, 3
  • Park, Donghwi1
  • Jo, Myungjin1
  • Kim, Hyung-Jun4
  • Suk, Kyoungho1, 2, 3
  • 1 Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu 41944, Korea. , (North Korea)
  • 2 BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Sciences, School of Medicine, Kyungpook National University, Daegu 412944, Korea. , (North Korea)
  • 3 Brain Science & Engineering Institute, Kyungpook National University, Daegu 41566, Korea. , (North Korea)
  • 4 Dementia Research Group, Korea Brain Research Institute (KBRI), Daegu 41062, Korea. , (North Korea)
Type
Published Article
Journal
Cells
Publisher
MDPI AG
Publication Date
Mar 18, 2021
Volume
10
Issue
3
Identifiers
DOI: 10.3390/cells10030676
PMID: 33803845
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Transactive response DNA-binding protein 43 (TDP-43) is a ubiquitously expressed DNA/RNA-binding protein linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 has been implicated in numerous aspects of the mRNA life cycle, as well as in cell toxicity and neuroinflammation. In this study, we used the toxicity of the TDP-43 expression in Saccharomyces cerevisiae as an assay to identify TDP-43 genetic interactions. Specifically, we transformed human TDP-43 cDNAs of wild-type or disease-associated mutants (M337V and Q331K) en masse into 4653 homozygous diploid yeast deletion mutants and then used next-generation sequencing readouts of growth to identify yeast toxicity modifiers. Genetic interaction analysis provided a global view of TDP-43 pathways, some of which are known to be involved in cellular metabolic processes. Selected putative loci with the potential of genetic interactions with TDP-43 were assessed for associations with neurotoxicity and inflammatory activation of astrocytes. The pharmacological inhibition of succinate dehydrogenase flavoprotein subunit A (SDHA) and voltage-dependent anion-selective channel 3 (VDAC3) suppressed TDP-43-induced expression of proinflammatory cytokines in astrocytes, indicating the critical roles played by SDHA and VDAC3 in TDP-43 pathways during inflammatory activation of astrocytes and neuroinflammation. Thus, the findings of our TDP-43 genetic interaction screen provide a global landscape of TDP-43 pathways and may help improve our understanding of the roles of glia and neuroinflammation in ALS and FTD pathogenesis.

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