A multi-omic analysis of optineurin proteinopathy in a yeast model suggests the involvement of lipid metabolism in Amyotrophic Lateral Sclerosis
A multi-omic analysis of optineurin proteinopathy in a yeast model suggests the involvement of lipid metabolism in Amyotrophic Lateral Sclerosis
Abstract Amyotrophic Lateral Sclerosis (ALS) is an incurable fatal neurodegenerative disease for which the precise mechanisms of toxicity remain unclear despite some significant advances in our understanding of the underlying genetic basis. A holistic, integrated view of cellular changes will be critical to understanding the processes of neurodegeneration and the development of effective treatments. Mutant forms of optineurin (a ubiquitin-binding protein involved in autophagy, membrane trafficking, and NF-κB activation) are found associated with cytoplasmic inclusions containing TDP43 or SOD1 in some ALS patients. We have taken a multi-omics approach to understand the cellular response to OPTN overexpression in a yeast model of ALS. We found that genetic interaction screens and metabolomics provided parallel, highly complementary data on OPTN toxicity. Genetic enhancers of OPTN toxicity in yeast relate directly to the native function of OPTN in vesicular trafficking and intracellular transport, suggesting the human OPTN protein is functional when expressed in yeast even though there is no yeast ortholog. Crucially, we find that the genetic modifiers and the metabolic response are distinct for different ALS-linked genes expressed in yeast. This lends strong support to the use of yeast as a model system and omics platform to study ALS.
Bean Daniel M.、Lilley Kathryn S.、Ralser Markus、Oliver Stephen G.、M¨1lleder Michael、Goodfellow Brian J.、Magalh?es Sandra、Nightingale Daniel J. H.、Nunes Alexandra、Hntova Silvia
King?ˉs College London, Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience||Cambridge Systems Biology Centre, University of Cambridge||Department of Biochemistry, University of CambridgeCambridge Centre for Proteomics, Department of Biochemistry, University of CambridgeCambridge Systems Biology Centre, University of Cambridge||Department of Biochemistry, University of CambridgeCambridge Systems Biology Centre, University of Cambridge||Department of Biochemistry, University of CambridgeDepartment of Biochemistry, University of CambridgeCICECO & Department of Chemistry, Campus Universit¨￠rio de Santiago, University of AveiroiBiMED & Department of Medical Sciences, Campus Universit¨￠rio de Santiago, University of Aveiro||CICECO & Department of Chemistry, Campus Universit¨￠rio de Santiago, University of AveiroiBiMED & Department of Medical Sciences, Campus Universit¨￠rio de Santiago, University of Aveiro||CICECO & Department of Chemistry, Campus Universit¨￠rio de Santiago, University of AveiroCambridge Systems Biology Centre, University of Cambridge
神经病学、精神病学分子生物学生物科学研究方法、生物科学研究技术
ALSSystems BiologyMetabolomics
Bean Daniel M.,Lilley Kathryn S.,Ralser Markus,Oliver Stephen G.,M¨1lleder Michael,Goodfellow Brian J.,Magalh?es Sandra,Nightingale Daniel J. H.,Nunes Alexandra,Hntova Silvia.A multi-omic analysis of optineurin proteinopathy in a yeast model suggests the involvement of lipid metabolism in Amyotrophic Lateral Sclerosis[EB/OL].(2025-03-28)[2025-04-30].https://www.biorxiv.org/content/10.1101/605998.点此复制
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