Aggregation of -synuclein and its presence as the dominant protein in Lewy bodies (LB) is a hallmark of a group of neurodegenerative diseases classified as the synucleinopathies. in their assembly and stability dependent on the phosphorylation state of the protein. In disease-affected neurons, hyperphosphorylation leads to the accumulation of the tau protein into aggregates, mainly neurofibrillary tangles (NFT) which have been seen to colocalise with other protein aggregates in neurodegeneration. One such protein is -synuclein, the main constituent of Lewy bodies (LB), a hallmark of Parkinsons disease (PD). In many neurodegenerative diseases, including PD, the colocalisation of tau and -synuclein has been observed, suggesting possible interactions between the two proteins. To explore the cytotoxicity and interactions between these two proteins, we expressed full length human tau and -synuclein in alone, and in combination. We show that tau is phosphorylated in and colocalises closely (within 40 nm) with tubulin throughout the cytoplasm of the cell as well as with -synuclein at the cortex. Expressing wild type -synuclein alone caused inhibited growth on bacterial lawns, phagocytosis and intracellular proliferation rates, but activated mitochondrial Dienestrol respiration and non-mitochondrial oxygen consumption. The expression of tau alone impaired multicellular morphogenesis, axenic growth and phototaxis, while enhancing intracellular proliferation. Direct respirometric assays showed that tau impairs mitochondrial ATP synthesis and increased the proton leak, while having no impact on respiratory complex I or II function. In most cases depending on the phenotype, the coexpression of tau and -synuclein exacerbated Dienestrol (phototaxis, fruiting body morphology), or reversed (phagocytosis, growth on plates, mitochondrial respiratory function, proliferation) the defects caused by either tau or -synuclein expressed individually. Proteomics data revealed distinct patterns of dysregulation in strains ectopically expressing tau or -synuclein or both, but down regulation of expression of cytoskeletal proteins was apparent in all three groups and most evident in the strain expressing both proteins. These results indicate that tau and -synuclein exhibit different but overlapping patterns of intracellular localisation, that they individually exert distinct but overlapping patterns of cytotoxic effects and that they interact, probably physically in the cell cortex as well as directly or indirectly in affecting some phenotypes. The results show the efficacy of using as a model to study the interaction of proteins involved in neurodegeneration. gene, is 140 amino acids in length and like tau is richly expressed in neurons. Aggregation of -synuclein and its presence as the dominant protein in Lewy bodies (LB) is a hallmark of a group of neurodegenerative diseases classified as the synucleinopathies. PD is the most common synucleinopathy but other diseases include Lewy Body Dementia, multiple system atrophy, and Parkinsonism with dementia (Galpern and Lang, 2006; Savica et al., 2013). -Synuclein is the most abundant aggregated protein in these disorders although other proteins like tau have been seen to colocalise within these aggregates as well suggesting an overlap of the tau- and synuclein-opathies. There have been many neurodegenerative diseases in which tau and -synuclein have Dienestrol been found to coexist, and several lines of evidence suggest an interaction between the two proteins. Colocalisation of tau and -synuclein has been seen in both NFT and LB (Arima et al., 2000; Ishizawa et al., 2003). -synuclein containing LB were seen to be present in AD brains over 50% of the time (Hamilton, 2000), in Downs syndrome brains with AD 50% of the time (Lippa et al., 1999) and found with PHF of tau in the same neurons (Iseki et al., 1999). The C-terminus of -synuclein has been seen to bind to the MT Binding Domain of tau promoting phosphorylation by protein-kinase A (Jensen et al., 1999). experiments using human cell lines have shown that tau and -synuclein can promote the aggregation of each other and increase cytotoxicity (Badiola et al., 2011; Castillo-Carranza et al., 2018). The application of models to study Dienestrol the interaction of the proteins has proved useful and support an interaction. A transgenic mouse model of PD overexpressing -synuclein increased tau phosphorylation and hyperphosphorylation and aggregates Dienestrol similar to LB were formed containing both tau and -synuclein (Haggerty et al., 2011). In is a novel eukaryotic model organism recognised by the National Institute of Health (NIH) in the United States for its importance in biomedical research. It has been used as a biomedical model for studying human diseases including neurodegeneration, lysosomal trafficking disorders and mitochondrial disease (Annesley and Fisher, 2009a; Francione et al., 2011; Maniak, 2011; Martn-Gonzlez et al., 2021). The complete nuclear (Eichinger et al., 2005) and also mitochondrial (Ogawa et al., 2000) genomes have been sequenced, allowing for orthologues of human genes to be studied. Of interest is the distinctive life cycle of in HPTA which there are both unicellular and multicellular stages with numerous cell types. This allows.