Identification of Genetic Modifiers of TDP-43: Inflammatory Activation of Astrocytes for Neuroinflammation
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 neuroinflam...
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MDPI AG
2021-03-01
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| author | Jae-Hong Kim Md Habibur Rahman Donghwi Park Myungjin Jo Hyung-Jun Kim Kyoungho Suk |
| author_facet | Jae-Hong Kim Md Habibur Rahman Donghwi Park Myungjin Jo Hyung-Jun Kim Kyoungho Suk |
| author_sort | Jae-Hong Kim |
| collection | DOAJ |
| description | 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 <i>Saccharomyces cerevisiae</i> as an assay to identify <i>TDP-43</i> genetic interactions. Specifically, we transformed human <i>TDP-43</i> cDNAs of wild-type or disease-associated mutants (<i>M337V</i> and <i>Q331K</i>) 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 <i>TDP-43</i> 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 <i>TDP-43</i> 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. |
| first_indexed | 2024-03-10T13:06:31Z |
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| language | English |
| last_indexed | 2024-03-10T13:06:31Z |
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| spelling | doaj.art-2a5e4c847e3b486d9a2cb6df3b4dc8302023-11-21T11:04:38ZengMDPI AGCells2073-44092021-03-0110367610.3390/cells10030676Identification of Genetic Modifiers of TDP-43: Inflammatory Activation of Astrocytes for NeuroinflammationJae-Hong Kim0Md Habibur Rahman1Donghwi Park2Myungjin Jo3Hyung-Jun Kim4Kyoungho Suk5Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu 41944, KoreaDepartment of Pharmacology, School of Medicine, Kyungpook National University, Daegu 41944, KoreaDepartment of Pharmacology, School of Medicine, Kyungpook National University, Daegu 41944, KoreaDepartment of Pharmacology, School of Medicine, Kyungpook National University, Daegu 41944, KoreaDementia Research Group, Korea Brain Research Institute (KBRI), Daegu 41062, KoreaDepartment of Pharmacology, School of Medicine, Kyungpook National University, Daegu 41944, KoreaTransactive 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 <i>Saccharomyces cerevisiae</i> as an assay to identify <i>TDP-43</i> genetic interactions. Specifically, we transformed human <i>TDP-43</i> cDNAs of wild-type or disease-associated mutants (<i>M337V</i> and <i>Q331K</i>) 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 <i>TDP-43</i> 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 <i>TDP-43</i> 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.https://www.mdpi.com/2073-4409/10/3/676TDP-43astrocyteglianeuroinflammationgenetic interactionamyotrophic lateral sclerosis |
| spellingShingle | Jae-Hong Kim Md Habibur Rahman Donghwi Park Myungjin Jo Hyung-Jun Kim Kyoungho Suk Identification of Genetic Modifiers of TDP-43: Inflammatory Activation of Astrocytes for Neuroinflammation Cells TDP-43 astrocyte glia neuroinflammation genetic interaction amyotrophic lateral sclerosis |
| title | Identification of Genetic Modifiers of TDP-43: Inflammatory Activation of Astrocytes for Neuroinflammation |
| title_full | Identification of Genetic Modifiers of TDP-43: Inflammatory Activation of Astrocytes for Neuroinflammation |
| title_fullStr | Identification of Genetic Modifiers of TDP-43: Inflammatory Activation of Astrocytes for Neuroinflammation |
| title_full_unstemmed | Identification of Genetic Modifiers of TDP-43: Inflammatory Activation of Astrocytes for Neuroinflammation |
| title_short | Identification of Genetic Modifiers of TDP-43: Inflammatory Activation of Astrocytes for Neuroinflammation |
| title_sort | identification of genetic modifiers of tdp 43 inflammatory activation of astrocytes for neuroinflammation |
| topic | TDP-43 astrocyte glia neuroinflammation genetic interaction amyotrophic lateral sclerosis |
| url | https://www.mdpi.com/2073-4409/10/3/676 |
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