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

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.

Vitamin B6, B12 and folate modulate deregulated pathways and protein aggregation in yeast model of Huntington disease.

Huntington's disease (HD) is an incurable and progressive neurodegenerative disease affecting the basal ganglia of the brain. HD is caused due to expansion of the polyglutamine tract in the protein Huntingtin resulting in aggregates. The increased PolyQ length results in aggregation of protein Huntingtin leading to neuronal cell death. Vitamin B6, B12 and folate are deficient in many neurodegenerative diseases. We performed an integrated analysis of transcriptomic, metabolomic and cofactor-protein network of vitamin B6, B12 and folate was performed. Our results show considerable overlap of pathways modulated by Vitamin B6, B12 and folate with those obtained from transcriptomic and metabolomic data of HD patients and model systems. Further, in yeast model of HD we showed treatment of B6, B12 or folate either alone or in combination showed impaired aggregate formation. Transcriptomic analysis of yeast model treated with B6, B12 and folate showed upregulation of pathways like ubiquitin mediated proteolysis, autophagy, peroxisome, fatty acid, lipid and nitrogen metabolism. Metabolomic analysis of yeast model shows deregulation of pathways like aminoacyl-tRNA biosynthesis, metabolism of various amino acids, nitrogen metabolism and glutathione metabolism. Integrated transcriptomic and metabolomic analysis of yeast model showed concordance in the pathways obtained. Knockout of Peroxisomal (PXP1 and PEX7) and Autophagy (ATG5) genes in yeast increased aggregates which is mitigated by vitamin B6, B12 and folate treatment. Taken together our results show a role for Vitamin B6, B12 and folate mediated modulation of pathways important for preventing protein aggregation with potential implications for HD. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03525-y.

Integrated network pharmacology approach shows a potential role of Ginseng catechins and ginsenosides in modulating protein aggregation in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral Sclerosis is an incurable, progressive neurodegenerative motor neuron disease. The disease is characterized by protein aggregates. The symptoms include weakness, denervation of muscles, atrophy and progressive paralysis of bulbar and respiratory muscles and dysphagia. Various secondary metabolites are evaluated for their ability to improve symptoms in ALS. Ginseng has been traditionally used for treating several neurodegenerative diseases. Several studies using model systems have shown a potential role of Ginseng catechins and Ginsenosides in clearing protein aggregation associated with ALS. We focus on Network pharmacology approach to understand the effect of Ginseng catechins or ginsenosides on protein aggregation associated with ALS. A catechin/ginsenoside-protein interaction network was generated and the pathways obtained were compared with those obtained from transcriptomic datasets of ALS from GEO database. Knock out of MAPK14, AKT and GSK from Catechin and BACE 1 from ginsenoside modulated pathways inhibited protein aggregation. Catechins and ginsenosides have potential as therapeutic agents in the management of ALS. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-022-03401-1.