In the last decade, the budding yeast Saccharomyces cerevisiae
has been used as a model system to gain insights about the mechanisms of neurodegenerative disorders such as Parkinson's, Huntington's, and Alzheimer's [72
]. Yeast cells are generally used to study key proteins involved in the etiology and/or pathology of these diseases. When a yeast homologue exists, the corresponding gene can be easily disrupted or overexpressed to determine the loss or gain of function phenotypes, respectively. When a yeast homologue is not present, the human gene can be expressed in yeast and any relevant phenotype that results from this expression can be analyzed. The latter has been called humanized yeast models [73
]. Despite their simplicity, yeast cells possess most of the same basic cellular machinery as neurons in the brain, including pathways required for protein homeostasis and energy metabolism. Also their easy genetic manipulation makes these cells an ideal tool for molecular biology.
Many of the genes and biological systems that function in yeast Fe homeostasis are conserved throughout eukaryotes to humans [74
]. S. cerevisiae
expresses three genetically distinct transport systems for Fe, two reductive systems and one nonreductive system. The reductive Fe uptake system consists in a low-affinity pathway defined by Fet4, that can also transport other metals and in a high-affinity pathway that is mediated by a protein complex composed of a multicopper ferroxidase Fet3, the mammalian Cp homologue, and a permease Ftr1. The Fet3-Ftr1 complex is specific for Fe and is regulated both transcriptionally and posttranscriptionally by this metal [75
]. The nonreductive Fe uptake system is mediated by the ARN family (Arn1-4) of membrane permeases that transport siderophore-Fe3+
]. Additionally Harris et al. [80
] showed for the first time that Fet3 can functionally replace ceruloplasmin in restoring Fe homeostasis.
Moreover, cells are able to spare Fe through the regulation of Tis11 homologues and Cth1/2-mediated degradation of mRNAs coding for Fe-binding proteins, thereby facilitating the utilization of limited cellular Fe levels [81
Since S. cerevisiae
lacks the Fe storage protein, ferritin, during Fe overload this is sequestered into the vacuole by the Ccc1 transporter, which is under the control of the Yap5 transcription factor [13
]. On the other hand, Fet5/Fth1 complex mobilizes Fe out of the vacuole for use during Fe limitation [83
Given the similarities between yeast and mammals and the availability of humanized S. cerevisiae strains, yeast could potentially become an effective model to dissect the molecular pathway associated with the misregulation of Fe homeostasis in the neurodegenerative diseases.
One good example of the use of yeast to study Fe accumulation in a neurodegenerative disease was first reported for Friedreich's ataxia (FRDA). FRDA is an autosomal recessive mitochondrial disorder that causes progressive damage to the nervous system, resulting in gait disturbance, speech problems, heart disease, and diabetes. It is caused by GAA triplet expansion in the first intron of the frataxin gene (FA
A gene with high sequence similarity to FA
was initially identified in yeast, the yeast frataxin homologue, YFH1
] and later it was shown that the two proteins were both located in the mitochondria. Moreover, human FA
could complement for the absence of the yeast yfh1
]. However, FA
function was only discovered when Lodi and coworkers [87
] showed that the YFH1
knockout strain led to an excessive Fe accumulation in the mitochondria resulting in the generation of ROS and consequently oxidative damage. The yeast frataxin homologue provided the evidence that FRDA is indeed a mitochondrial disorder. The yeast model allowed a better understanding of the FDRA pathophysiology and provided a tool for assaying therapeutic targets.