Yeast as a Model System to Study Tau Biology

Table 1

Cellular processes involved in tau biology and/or pathology, and their amenability for study in the humanized yeast system. Readers should be aware that this table is not a complete overview of all cellular processes involved in tau biology/pathology and is meant to illustrate some opportunities and limitations of the humanized yeast system. Note the multitude of processes and orthologues, not yet studied in yeast at present.

Processes involved in tau biology/pathology	Opportunity for humanized yeast system?
Kinases/phosphatases determining the phosphorylation status of tau	(i) Multitude of phosphotau species demonstrated in yeast (see Figure 3 and [84]); (ii) Yeast orthologues of important tau kinases; (1) Gsk-3β (Mds1) (studied in [84–86]); (2) Cdk5 (Pho85) (studied in [84–86]); (3) PKA (Tpk1-3); (4) CaMKII (Cmk1/Cmk2); (iii) Yeast orthologues of important tau phosphatases; (1) PP1 (Glc7); (2) PP2A (Pph21/Pph22, Sit4); (iv) Yeast orthologue of Pin1 (Ess1)
Tau mutations	Several clinical FTDP-17 tau mutants have been expressed in yeast, and the effects of their mutation on tau phosphorylation and aggregation have been investigated [86]
Effect of oxidative stress and/or mitochondrial dysfunction on tau pathology	Both oxidative stress and mitochondrial dysfunction are amenable to yeast studies; (i) Fe^2+-induced oxidative stress increases tau aggregation (SinT) in yeast [86]; (ii) Tau aggregation (SinT) is increased in mitochondrial mutants sod2Δ and rim1Δ [86]
Tau binding to; (i) MT; (ii) Actin; (iii) (plasma) membrane	(i) Binding of tau to yeast MT not (yet) demonstrated, although tau purified from yeast binds to mammalian (pig) MT in vitro [85, 86]; (ii) Binding of tau to yeast actin cytoskeleton is not yet investigated; (iii) Binding of tau to yeast plasma membrane or other intracellular membranes is not yet studied
Processes involved in tau clearance; (i) apoptosis/caspase-cleavage of tau; (ii) ubiquitin-proteasome system; (iii) autophagic-lysosomal system	All these processes are present in yeast and can thus be studied for their effects on tau biology in the humanized yeast system; Note: yeast does not contain true orthologues of mammalian caspases, though it contains a caspase-related protease Yca1 (termed “meta”caspase), involved in yeast apoptosis [87]. The cleavage-specificity of caspases (cleave after aspartic acid) is different from that of metacaspases (cleave after arginine or lysine)
Aging	Stationary-phase yeast can serve as a model for aging effects. Not yet studied for effects on tau biology/pathology in the humanized yeast system
Aberrant cellular signalling	As tau has no apparent yeast orthologue, yeast cellular signalling pathways are intrinsically independent on normal tau functioning. Neuron-specific, tau-dependent signalling pathways are therefore not amenable for studies in yeast
Inflammation	Not applicable for studies in yeast. Though we note that one of the major consequences of inflammation is the generation of oxidative stress, which can be studied in a yeast environment