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-{kappa}B 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.