Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The VSports app下载. gov means it’s official. Federal government websites often end in . gov or . mil. Before sharing sensitive information, make sure you’re on a federal government site. .

Https

The site is secure V体育官网. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely. .

. 2023 Apr 24;12(9):1228.
doi: 10.3390/cells12091228.

VSports注册入口 - Integrated Omic Analysis Delineates Pathways Modulating Toxic TDP-43 Protein Aggregates in Amyotrophic Lateral Sclerosis

Saiswaroop Rajaratnam  1 , Akhil P Soman  1   2 , Kanikaram Sai Phalguna  1 , Sai Sanwid Pradhan  1 , Meghana Manjunath  3 , Raksha Kanthavara Rao  3 , Rajesh Babu Dandamudi  4 , Sai Krishna Srimadh Bhagavatham  1 , Sujith Kumar Pulukool  1 , Sriram Rathnakumar  1 , Sai Kocherlakota  5 , Ashish Pargaonkar  6 , Ravindra P Veeranna  7 , Natarajan Arumugam  8 , Abdulrahman I Almansour  8 , Bibha Choudhary  3 , Venketesh Sivaramakrishnan  1
Affiliations

Integrated Omic Analysis Delineates Pathways Modulating Toxic TDP-43 Protein Aggregates in Amyotrophic Lateral Sclerosis

Saiswaroop Rajaratnam et al. Cells. .

Abstract

Amyotrophic lateral sclerosis (ALS) is a multi-systemic, incurable, amyloid disease affecting the motor neurons, resulting in the death of patients. The disease is either sporadic or familial with SOD1, C9orf72, FUS, and TDP-43 constituting the majority of familial ALS. Multi-omics studies on patients and model systems like mice and yeast have helped in understanding the association of various signaling and metabolic pathways with the disease. The yeast model system has played a pivotal role in elucidating the gene amyloid interactions. We carried out an integrated transcriptomic and metabolomic analysis of the TDP-43 expressing yeast model to elucidate deregulated pathways associated with the disease. The analysis shows the deregulation of the TCA cycle, single carbon metabolism, glutathione metabolism, and fatty acid metabolism. Transcriptomic analysis of GEO datasets of TDP-43 expressing motor neurons from mice models of ALS and ALS patients shows considerable overlap with experimental results. Furthermore, a yeast model was used to validate the obtained results using metabolite addition and gene knock-out experiments VSports手机版. Taken together, our result shows a potential role for the TCA cycle, cellular redox pathway, NAD metabolism, and fatty acid metabolism in disease. Supplementation of reduced glutathione, nicotinate, and the keto diet might help to manage the disease. .

Keywords: ALS; metabolomics; neurodegenerative disease; protein aggregates; transcriptomics. V体育安卓版.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(A) Fluorescence images (dark field, bright field and overlay) showing Saccharomyces cerevisiae transformed with TDP-43 and its mutant. (B) Heat map representing differentially expressed significant metabolites obtained from TDP-43-Q331K Mutant (Water’s Amide Column-Positive Mode-4 biological replicates). (C) Heat map representing differentially expressed significant metabolites obtained from TDP-43-Q331K Mutant (Water’s Amide Column-Negative Mode-3 biological replicates) (Two Tailed t-test FDR corrected p-value of 0.25) (Figures were made using www.metaboanalyst.ca, Version 5.0).
Figure 2
Figure 2
(A) Table representing details about number of significant genes obtained after transcriptomic analysis of TDP-43-Q331K Mutant (Adj.P-Value ≤ 0.05–3 replicates). (B) Bar graphs representing expression levels of CIT3, MIH1, and FAA2 from transcriptomics and RT-PCR. (C) Results representing GSEA results from RNA sequencing of Saccharomyces cerevisiae transfected with TDP-43-Q331K Mutant. (Figures were made using www.networkanalyst.ca (Version 5.0) and Microsoft Excel 2019). (D) Results obtained from pathway enrichment analysis of transcriptomic data obtained from RNA sequencing of Saccharomyces cerevisiae transfected with TDP-43 and its mutant using Enrichr and KEGG database (www.maayanlab.cloud/Enrichr and Microsoft Excel 2019).
Figure 3
Figure 3
Results of integrated pathway enrichment analysis carried out for the enriched genes and metabolites. The colours in the graph represented gives the significance of the enriched pathways. Red represents high significance values and yellow represents lower significance levels. The size represents the impact of the pathway in the disease condition (Figures were made using www.metaboanalyst.ca, (Version 5.0)).
Figure 4
Figure 4
Heat map representing differentially expressed significant metabolites obtained from TDP-43-G294A Mutant (Water’s Amide Column-Positive Mode-4 biological replicates) (Figures were made using www.metaboanalyst.ca, Version 5.0).
Figure 5
Figure 5
(A) Heat map representing differentially expressed significant metabolites obtained from TDP-43-M337V Mutant (Water’s Amide Column-Positive Mode-4 biological replicates) (Figures were made using www.metaboanalyst.ca, Version 5.0). (B) Common metabolites obtained between different TDP-43 mutants (Figure was made using: www.bioinfogp.cnb.csic.es/tools/venny version 2.1).
Figure 6
Figure 6
Venn diagram representing common metabolic pathways (metabolomics) enriched by significant metabolites between TDP-43-Q331K, TDP-43-M337V, TDP-43-G294A Mutant and KEGG database (Figure was made using: www.bioinfogp.cnb.csic.es/tools/venny, Version 2.1).
Figure 7
Figure 7
(A) Venn diagram representing common metabolic pathways (transcriptomics) enriched between TDP-43 A315T Mutant—Mice [GSE111775] and TDP-43 Q331K Mutant and ALS patient cortex sections [GSE124439] (KEGG database) (Figure was made using www.bioinfogp.cnb.csic.es/tools/venny, Version 2.1). (B) Venn diagram representing common metabolic pathways (metabolomics) enriched between TDP-43 A315T Mutant (Mice) and TDP-43 mutants (Q331K, M337V and G294A) and ALS patient CSF. (KEGG database) (Figure was made using www.bioinfogp.cnb.csic.es/tools/venny, Version 2.1).
Figure 8
Figure 8
(A) Results of metabolite addition experiments show that TCA cycle metabolites increase amyloidogenesis in Saccharomyces cerevisiae transformed with TDP-43 and its mutant. ΔKGD10 and ΔMDH2 reduced amyloidogenesis. Fluorescence quantification results are provided in Tables S14–S21. Results of metabolite addition experiments (dark field, bright field and overlay) show that reduced glutathione reduced amyloidogenesis, while oxidized glutathione increased amyloidogenesis in Saccharomyces cerevisiae transformed with TDP-43 and its mutant. Treatment with nicotinic acid was found to attenuate amyloidogenesis. Fluorescence quantification results are provided in Tables S14–S21. (B) Imaging results (dark field, bright field and overlay) of metabolite addition experiments show that short-chain fatty acids reduce amyloidogenesis, while long-chain fatty acids increase amyloidogenesis in Saccharomyces cerevisiae transformed with TDP-43 and its mutant. (C) Figure representing images of filter retardation assay carried out on treated Saccharomyces cerevisiae transformed with TDP-43 and its mutant. Butyric acid showed complete absence of aggregates, while palmitic acid showed increased protein aggregates.
See this image and copyright information in PMC

V体育ios版 - References

    1. Tandan R., Bradley W.G. Amyotrophic lateral sclerosis: Part 1. Clinical features, pathology, and ethical issues in management. Ann. Neurol. 1985;18:271–280. doi: 10.1002/ana.410180302. - DOI - PubMed
    1. Koo E.H., Lansbury P.T., Jr., Kelly J.W. Amyloid diseases: Abnormal protein aggregation in neurodegeneration. Proc. Natl. Acad. Sci. USA. 1999;96:9989–9990. doi: 10.1073/pnas.96.18.9989. - DOI - PMC - PubMed
    1. Blokhuis A.M., Groen E.J.N., Koppers M., Berg L.H.V.D., Pasterkamp R.J. Protein aggregation in amyotrophic lateral sclerosis. Acta Neuropathol. 2013;125:777–794. doi: 10.1007/s00401-013-1125-6. - "VSports注册入口" DOI - PMC - PubMed
    1. Mathis S., Goizet C., Soulages A., Vallat J.-M., Le Masson G. Genetics of amyotrophic lateral sclerosis: A review. J. Neurol. Sci. 2019;399:217–226. doi: 10.1016/j.jns.2019.02.030. - DOI - PubMed
    1. McCann E.P., Henden L., Fifita J.A., Zhang K.Y., Grima N., Bauer D.C., Fat S.C.M., Twine N.A., Pamphlett R., Kiernan M.C., et al. Evidence for polygenic and oligogenic basis of Australian sporadic amyotrophic lateral sclerosis. J. Med. Genet. 2021;58:87–95. doi: 10.1136/jmedgenet-2020-106866. - DOI - PubMed

"V体育官网" Publication types

MeSH terms

LinkOut - more resources