Integrated multi-omic data analysis and validation with yeast model show oxidative phosphorylation modulates protein aggregation in amyotrophic lateral sclerosis

Swaroop, R Sai; Akhil, P S; Pradhan, Sai Sanwid; Bandana, Prasad; Raksha, Rao K; Manjunath, Meghana; Choudhary, Bibha; Sivaramakrishnan, Venketesh

doi:10.1080/07391102.2022.2090441

Cited by 14 publications

(7 citation statements)

References 92 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The yeast, human, and mice datasets exhibited an overlap of 2 pathways, which included ribosome and oxidative phosphorylation. Previous studies in our lab have shown that oxidative phosphorylation modulated TDP-43 aggregation in the yeast model of ALS [26]. Similarly, flavonoids from Ginseng were also shown to target the MAPK pathway [27].…”

Section: Discussionmentioning

confidence: 64%

“…Our previous analysis showed oxidative phosphorylation as a common deregulated pathway. Further, inhibitors of complex III and IV, or the knock-out of genes in these complexes (QCR8 and COX8), significantly reduced protein aggregation [26]. The mitochondrial dysfunction results in the generation of ROS, which is also associated with oxidative stress [59].…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies using the yeast model of FUS and TDP-43-mediated ALS have shown the role of genes in deregulated pathways as modifiers of protein aggregation or toxicity [3]. Previous studies have demonstrated a role for oxidative phosphorylation in FUS, and TDP-43 aggregation in the yeast model of ALS [26]. Further, network-based pharmacology approach has been used to evaluate the role of flavonoids and ginsenosides on FUS and TDP-43 aggregation in ALS [27].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Saiswaroop

Soman

Phalguna

et al. 2023

Cells

Self Cite

View full text Add to dashboard Cite

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. 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.

show abstract

Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Saiswaroop

Soman

Phalguna

et al. 2023

Cells

Self Cite

View full text Add to dashboard Cite

show abstract

“…The deletion of YBH3 , a gene involved in mitochondria‐dependent apoptosis, also reduced TDP‐43 toxicity. Transgenic mice datasets of SOD1, FUS, and TDP‐43 have also shown a deregulation in oxidative phosphorylation, a result that was validated in a yeast model system via inhibitor studies (Sai Swaroop et al, 2022). These inhibitor studies indicated that the inhibition of mitochondrial complex‐III and complex‐IV reduced protein aggregation and that deletion of QCR8 and COX8 , the genes encoding for complex‐III and complex‐IV respectively, cleared aggregates.…”

Section: Amyotrophic Lateral Sclerosismentioning

confidence: 86%

Saccharomyces cerevisiae as a research tool for RNA‐mediated human disease

Gastelum,

Michael,

Bolger

2023

WIREs RNA

View full text Add to dashboard Cite

The budding yeast, Saccharomyces cerevisiae, has been used for decades as a powerful genetic tool to study a broad spectrum of biological topics. With its ease of use, economic utility, well‐studied genome, and a highly conserved proteome across eukaryotes, it has become one of the most used model organisms. Due to these advantages, it has been used to study an array of complex human diseases. From broad, complex pathological conditions such as aging and neurodegenerative disease to newer uses such as SARS‐CoV‐2, yeast continues to offer new insights into how cellular processes are affected by disease and how affected pathways might be targeted in therapeutic settings. At the same time, the roles of RNA and RNA‐based processes have become increasingly prominent in the pathology of many of these same human diseases, and yeast has been utilized to investigate these mechanisms, from aberrant RNA‐binding proteins in amyotrophic lateral sclerosis to translation regulation in cancer. Here we review some of the important insights that yeast models have yielded into the molecular pathology of complex, RNA‐based human diseases.This article is categorized under: RNA in Disease and Development > RNA in Disease

show abstract

“…Our multi-omic analysis revealed AD is associated with mitochondrial dysfunction as well as deregulation of pathways like pyruvate metabolism, TCA cycle and nucleotide metabolism, and glutamine and glutamate metabolism. Previous studies in yeast model of ALS has shown that either inhibition or knock out (KO) of genes in complex III and IV lead to clearance of protein aggregates 87 . mice model of AD has shown that KO of complex III gene led to reduce a-beta aggregation 88 .…”

Section: Discussionmentioning

confidence: 99%

Integrated multi-omics analysis of Alzheimer’s disease shows molecular signatures associated with disease progression and potential therapeutic targets

Kodam

Swaroop

Pradhan

et al. 2023

Sci Rep

Self Cite

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by the formation of amyloid plaques implicated in neuronal death. Genetics, age, and sex are the risk factors attributed to AD. Though omics studies have helped to identify pathways associated with AD, an integrated systems analysis with the available data could help to understand mechanisms, potential biomarkers, and therapeutic targets. Analysis of transcriptomic data sets from the GEO database, and proteomic and metabolomic data sets from literature was performed to identify deregulated pathways and commonality analysis identified overlapping pathways among the data sets. The deregulated pathways included those of neurotransmitter synapses, oxidative stress, inflammation, vitamins, complement, and coagulation pathways. Cell type analysis of GEO data sets showed microglia, endothelial, myeloid, and lymphoid cells are affected. Microglia are associated with inflammation and pruning of synapses with implications for memory and cognition. Analysis of the protein-cofactor network of B2, B6, and pantothenate shows metabolic pathways modulated by these vitamins which overlap with the deregulated pathways from the multi-omics analysis. Overall, the integrated analysis identified the molecular signature associated with AD. Treatment with anti-oxidants, B2, B6, and pantothenate in genetically susceptible individuals in the pre-symptomatic stage might help in better management of the disease.

show abstract

Integrated multi-omic data analysis and validation with yeast model show oxidative phosphorylation modulates protein aggregation in amyotrophic lateral sclerosis

Cited by 14 publications

References 92 publications

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

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

Saccharomyces cerevisiae as a research tool for RNA‐mediated human disease

Integrated multi-omics analysis of Alzheimer’s disease shows molecular signatures associated with disease progression and potential therapeutic targets

Contact Info

Product

Resources

About