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Article
L. Miguel Martins
University Of Cambridge
Corresponding Author
ORCiD: https://orcid.org/0000-0002-3019-4809
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This work is licensed under a CC BY 4.0 License. Read Full License
The innate immune response mounts a defence against foreign invaders, but the inappropriate induction of an innate immune response can cause diseases. Previous studies have provided ample evidence showing that mitochondria can be repurposed to promote inflammatory signalling. Damaged mitochondria can also trigger inflammation and promote diseases. Mutations in pink1 cause early-onset Parkinson’s disease (PD), and studies using Drosophila melanogaster have shown that pink1 mutants accumulate damaged mitochondria. Here, we showed that defective mitochondria in pink1 mutants activate Relish targets and demonstrated that inflammatory signalling causes intestinal dysfunction in pink1-mutant flies. These effects result in the death of intestinal cells and metabolic reprogramming, which leads to neurotoxicity. We found that Relish signalling is activated downstream of a pathway stimulated by cytosolic DNA. The suppression of Relish in the intestinal midgut of pink1-mutant flies restores mitochondrial function and protects neurons in the brain. We thus conclude that the gut-brain axis causes neurotoxicity in a fly model of PD through a mechanism involving mitochondrial dysfunction.
Keywords
Drosophila, mitochondria, Parkinson’s disease, pink1, Relish, innate immunity, intestine, brain, gut-brain communication
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There is NO Competing Interest.
This is a list of supplementary files associated with this preprint. Click to download.
- SupplementaryTable1.xlsx
Supplementary Table 1. Full complement of transcriptional changes in pink1-mutant flies. The fold-changes and p-values for each comparison are shown. P_val, uncorrected p-value; p_Adj_BH, p-value corrected using the Benjamini Hochberg method. This table is related to Figure 1B.
- SupplementaryTable2.xlsx
Supplementary Table 2. Full complement of protein changes in pink1-mutant flies. The individual quantitation levels are shown as log-transformed (base 2) intensity values from the mass spectrometer. Adj.P.Val, p-value corrected using the Benjamini Hochberg method. This table is related to Figures 1B and 6B.
- SupplementaryTable3.xlsx
Supplementary Table 3. Proteins mapped to transcripts that are potentially involved in the Drosophila immune response with altered expression in pink1 mutant flies. The fold-changes (FCs) and p-values for each comparison are shown. P_val, uncorrected p-value; p_Adj_BH, p-value corrected using the Benjamini Hochberg method. This table is related to Figure 1B.
- SupplementaryTable4.xlsx
Supplementary Table 4. In silico analysis of upstream regulators of Drosophila immune response transcripts that show altered expression in pink1-mutant flies. The analysis was performed using the iRegulon computational method in Cytoscape.
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This preprint is under consideration at a Nature Portfolio Journal. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Nature journals have partnered with Research Square to offer In Review, a journal-integrated preprint deposition service.
Article
L. Miguel Martins
University Of Cambridge
Corresponding Author
ORCiD: https://orcid.org/0000-0002-3019-4809
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 1
Posted 16 Dec, 2020
Metrics
Comments: 0
PDF Downloads: ...
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License:
This work is licensed under a CC BY 4.0 License. Read Full License
The innate immune response mounts a defence against foreign invaders, but the inappropriate induction of an innate immune response can cause diseases. Previous studies have provided ample evidence showing that mitochondria can be repurposed to promote inflammatory signalling. Damaged mitochondria can also trigger inflammation and promote diseases. Mutations in pink1 cause early-onset Parkinson’s disease (PD), and studies using Drosophila melanogaster have shown that pink1 mutants accumulate damaged mitochondria. Here, we showed that defective mitochondria in pink1 mutants activate Relish targets and demonstrated that inflammatory signalling causes intestinal dysfunction in pink1-mutant flies. These effects result in the death of intestinal cells and metabolic reprogramming, which leads to neurotoxicity. We found that Relish signalling is activated downstream of a pathway stimulated by cytosolic DNA. The suppression of Relish in the intestinal midgut of pink1-mutant flies restores mitochondrial function and protects neurons in the brain. We thus conclude that the gut-brain axis causes neurotoxicity in a fly model of PD through a mechanism involving mitochondrial dysfunction.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
There is NO Competing Interest.
This is a list of supplementary files associated with this preprint. Click to download.
- SupplementaryTable1.xlsx
Supplementary Table 1. Full complement of transcriptional changes in pink1-mutant flies. The fold-changes and p-values for each comparison are shown. P_val, uncorrected p-value; p_Adj_BH, p-value corrected using the Benjamini Hochberg method. This table is related to Figure 1B.
- SupplementaryTable2.xlsx
Supplementary Table 2. Full complement of protein changes in pink1-mutant flies. The individual quantitation levels are shown as log-transformed (base 2) intensity values from the mass spectrometer. Adj.P.Val, p-value corrected using the Benjamini Hochberg method. This table is related to Figures 1B and 6B.
- SupplementaryTable3.xlsx
Supplementary Table 3. Proteins mapped to transcripts that are potentially involved in the Drosophila immune response with altered expression in pink1 mutant flies. The fold-changes (FCs) and p-values for each comparison are shown. P_val, uncorrected p-value; p_Adj_BH, p-value corrected using the Benjamini Hochberg method. This table is related to Figure 1B.
- SupplementaryTable4.xlsx
Supplementary Table 4. In silico analysis of upstream regulators of Drosophila immune response transcripts that show altered expression in pink1-mutant flies. The analysis was performed using the iRegulon computational method in Cytoscape.
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