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

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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.
Author(s)
김재홍김형준박동휘석경호조명진하비브 라흐만
Issued Date
2021
Type
Article
Keyword
amyotrophic lateral sclerosisastrocytegenetic interactionglianeuroinflammationTDP-43
DOI
10.3390/cells10030676
URI
https://oak.ulsan.ac.kr/handle/2021.oak/8206
https://ulsan-primo.hosted.exlibrisgroup.com/primo-explore/fulldisplay?docid=TN_cdi_doaj_primary_oai_doaj_org_article_2a5e4c847e3b486d9a2cb6df3b4dc830&context=PC&vid=ULSAN&lang=ko_KR&search_scope=default_scope&adaptor=primo_central_multiple_fe&tab=default_tab&query=any,contains,Identification%20of%20Genetic%20Modifiers%20of%20TDP-43:%20Inflammatory%20Activation%20of%20Astrocytes%20for%20Neuroinflammation&offset=0&pcAvailability=true
Publisher
CELLS
Location
스위스
Language
한국어
ISSN
2073-4409
Citation Volume
10
Citation Number
3
Citation Start Page
676
Citation End Page
676
Appears in Collections:
Medicine > Medicine
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